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Corticotropin-Releasing Factor, Norepinephrine, and Stress
Abstract
Corticotropin-releasing factor (CRF) and related peptides in the central nervous system appears to have activating properties on behavior and to enhance behavioral responses to stressors. CRF and urocortin injected into the brain produces increases in arousal as measured by locomotor activation and increased responsiveness to stressful stimuli. These effects of CRF appear to be independent of the pituitary adrenal axis and can be reversed by specific and selective CRF antagonists alpha-helical CRF9-41 and D-Phe CRF12-41. Perhaps more importantly, CRF antagonists can reverse behavioral responses to many stressors. These results suggest that endogenous CRF systems in the brain may have a role in mediating behavioral responses to stressors. Norepinephrine systems emanating from the nucleus locus coeruleus also long have been hypothesized to be involved in mediating behavioral constructs associated with alertness, arousal, and stress. Pharmacologic, physiologic, and neuroanatomic evidence supports an important role for a CRF-norepinephrine interaction in the region of the locus coeruleus in response to stressors that may be modality-specific where CRF neurons activate the locus coeruleus. One may hypothesize that another norepinephrine-CRF interaction may occur in the terminal projections of the forebrain norepinephrine systems in the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central nucleus of the amygdala where norepinephrine stimulates CRF release. Such a feed-forward system may be particularly important in situations where an organism must mobilize not only the pituitary adrenal system but also the central nervous system, in response to environmental challenge. However, such a feed-forward mechanism in a fundamental brain-activating system may be particularly vulnerable to dysfunction and thus, may be the key to a variety of pathophysiologic conditions involving abnormal responses to stressors such as anorexia nervosa, anxiety, and affective disorders.
... and dopaminergic pathway in the brain (Koob, 1999;Ventriglio et al., 2015;van Bodegom et al., 2017). When a neonate is exposed to stress, biological activities are elevated to respond appropriately to the stress and participate in neurotransmitter delivery and shaping of neuronal circuits, ultimately resulting in persistent and pervasive alterations that manifest as detrimental psychological and behavioral outcomes (Agorastos et al., 2018). ...
... The released NE transmits signals globally to target organs governed by the central nervous system, including the adrenal medulla, cardiovascular system, respiratory system, and renal system, which results in behavioral changes. In the adrenal medulla, both NE and epinephrine, an analog of NE, are secreted and result in physiological responses (Koob, 1999;Herrmann et al., 2004;Morilak et al., 2005). These processes are controlled by negative feedback via the α2 adrenoreceptor, which inhibits NE release. ...
... These processes are controlled by negative feedback via the α2 adrenoreceptor, which inhibits NE release. In addition, HPA axis-related factors are involved in the activation of the autonomous nervous system (Koob, 1999). Pre-opiomelanocortin, a precursor polypeptide synthesized in corticotrophs of the anterior pituitary, produces ACTH, β-endorphin, and melatonin. ...
Early-life stress is associated with a high prevalence of mental illnesses such as post-traumatic stress disorders, attention-deficit/hyperactivity disorder, schizophrenia, and anxiety or depressive behavior, which constitute major public health problems. In the early stages of brain development after birth, events such as synaptogenesis, neuron maturation, and glial differentiation occur in a highly orchestrated manner, and external stress can cause adverse long-term effects throughout life. Our body utilizes multifaceted mechanisms, including neuroendocrine and neurotransmitter signaling pathways, to appropriately process external stress. Newborn individuals first exposed to early-life stress deploy neurogenesis as a stress-defense mechanism; however, in adulthood, early-life stress induces apoptosis of mature neurons, activation of immune responses, and reduction of neurotrophic factors, leading to anxiety, depression, and cognitive and memory dysfunction. This process involves the hypothalamus-pituitary-adrenal axis and neurotransmitters secreted by the central nervous system, including norepinephrine, dopamine, and serotonin. The rodent early-life stress model is generally used to experimentally assess the effects of stress during neurodevelopment. This paper reviews the use of the early-life stress model and stress response mechanisms of the body and discusses the experimental results regarding how early-life stress mediates stress-related pathways at a high vulnerability of psychiatric disorder in adulthood.
... Corticotropin-releasing factor (CRF), a 41 amino acid polypeptide that originates from the paraventricular nucleus of the hypothalamus, modulates stress-related effects in the central nervous system (CNS), such as alteration in wakefulness and sleep [9,10]. This peptide has a variety of biological effects and is an indicator of hypothalamic-pituitaryadrenal (HPA) axis activity [11][12][13]. ...
... When taurine and CRF were coadministered, there was no effect on temperature. Values are expressed as mean ± SEM from chick groups (8)(9)(10). Means with different superscripts indicate statistically significant differences (p < 0.05). ...
... No significant changes were detected in the time spent standing or sitting motionless with the eyes opened or the time spent standing motionless with the eyes closed ( Figure 2C,D). Values are expressed as mean ± SEM from the chick groups (9)(10). Means with different superscripts indicate statistically significant differences (p < 0.05). ...
The objective of this study was to determine the effects of centrally administered taurine on rectal temperature, behavioral responses and brain amino acid metabolism under isolation stress and the presence of co-injected corticotropin-releasing factor (CRF). Neonatal chicks were centrally injected with saline, 2.1 pmol of CRF, 2.5 μmol of taurine or both taurine and CRF. The results showed that CRF-induced hyperthermia was attenuated by co-injection with taurine. Taurine, alone or with CRF, significantly decreased the number of distress vocalizations and the time spent in active wakefulness, as well as increased the time spent in the sleeping posture, compared with the saline- and CRF-injected chicks. An amino acid chromatographic analysis revealed that diencephalic leucine, isoleucine, tyrosine, glutamate, asparagine, alanine, β-alanine, cystathionine and 3-methylhistidine were decreased in response to taurine alone or in combination with CRF. Central taurine, alone and when co-administered with CRF, decreased isoleucine, phenylalanine, tyrosine and cysteine, but increased glycine concentrations in the brainstem, compared with saline and CRF groups. The results collectively indicate that central taurine attenuated CRF-induced hyperthermia and stress behaviors in neonatal chicks, and the mechanism likely involves the repartitioning of amino acids to different metabolic pathways. In particular, brain leucine, isoleucine, cysteine, glutamate and glycine may be mobilized to cope with acute stressors.
... These hypotheses are not mutually excluding, and the control of synthesis and release of GCs could be a multifaceted system, not exclusively dependent on the activation/inhibition of the HPA axis [38]. In addition to GCs, the NE released by LC and NTS could act in brain nuclei such as the amygdala and PVH to maintain HPA activity [12,18,[39][40][41]. To our knowledge, for the first time, these results showed that the rise and release of NE are as vital as GCs, during every single stressor, to the establishment of the CUS-induced HPA axis hyperactivation. ...
... However, identifying its participation in maintaining chronic hyperactivation of the HPA axis is relatively recent [43,44]. Centrally released NE also plays an essential role in arousal and alertness [reviewed on [40]], and the dysregulation of the noradrenergic system could contribute to the susceptibility of stress-related illnesses. NE (systemically or centrally released) can excite CRF-containing cells in the PVH to activate the HPA axis. ...
... The interactions between CRF-and NE-containing neurons within the CNS are well established. Intracerebral administration of NE and adrenergic agonists can change the activity of CRF-containing neurons, and, conversely, administration of CRF can alter the activity of noradrenergic neurons [reviewed on [40]]. Here, we evidence the relevance of NE in this paradigm since our results showed that atenolol and phentolamine modulate the plasmatic CORT, GR levels, and CRF 2 mRNA expression in brain structures related to the HPA control in animals submitted to CUS. ...
The stress response is multifactorial and enrolls circuitries to build a coordinated reaction, leading to behavioral, endocrine, and autonomic changes. These changes are mainly related to the hypothalamus–pituitary–adrenal (HPA) axis activation and the organism’s integrity. However, when self-regulation is ineffective, stress becomes harmful and predisposes the organism to pathologies. The chronic unpredictable stress (CUS) is a widely used experimental model since it induces physiological and behavioral changes and better mimics the stressors variability encountered in daily life. Corticotropin-releasing factor (CRF) and glucocorticoids (GCs) are deeply implicated in the CUS-induced physiological and behavioral changes. Nonetheless, the CUS modulation of CRF receptors and GR and the norepinephrine role in extra-hypothalamic brain areas were not well explored. Here, we show that 14 days of CUS induced a long-lasting HPA axis hyperactivity evidenced by plasmatic corticosterone increase and adrenal gland hypertrophy, which was dependent on both GCs and NE release induced by each stress session. CUS also increased CRF2 mRNA expression and GR protein levels in fundamental brain structures related to HPA regulation and behavior, such as the lateral septal nucleus intermedia part (LSI), ventromedial hypothalamic nucleus (VMH), and central nucleus of the amygdala (CeA). We also showed that NE participates in the CUS-induced increase in CRF2 and GR levels in the LSI, reinforcing the locus coeruleus (LC) involvement in the HPA axis modulation. Despite the CUS-induced molecular changes in essential areas related to anxiety-like behavior, this phenotype was not observed in CUS animals 24 h after the last stress session.
... 92,93 Craving is commonly elicited by exposure to addictive drugs, stress, and environmental cues associated with drugtaking behavior, 35 activating the shared circuitry involving frontostriatal glutamatergic pathways, 36 the nucleus accumbens and related dopaminergic circuitry, [94][95][96] as well as the basolateral nucleus of the amygdala, the hippocampus, the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the noradrenergic nuclei in the brain stem, which are associated with norepinephrine and corticotropin-releasing factor (CRF) release during stress-induced activation of anti-reward pathways. [97][98][99][100] Loneliness may be relevant to all these triggers. When repeatedly paired with drugs, withdrawal-related stress, and environmental cues, loneliness can become a conditioned stimulus that independently triggers various forms of craving. ...
... The Methylenetetrahydrofolate reductase (MTHFR) C677T is another relevant polymorphism, which is linked to loneliness and reward deficiency, independent of age, education, cognitive function, and mood. 131,132 Stress plays an important role in addiction 98,133,134 and is also a part of loneliness experience. In older adults, the impact of stress inherent in rare contact with children and low levels of social support on loneliness is influenced by two SNPs, namely rs1876831 and rs242938, located within the corticotropin-releasing hormone receptor 1 (CRHR1) gene. ...
Loneliness, an established risk factor for both, mental and physical morbidity, is a mounting public health concern. However, the neurobiological mechanisms underlying loneliness-related morbidity are not yet well defined. Here we examined the role of genes and associated DNA risk polymorphic variants that are implicated in loneliness via genetic and epigenetic mechanisms and may thus point to specific therapeutic targets. Searches were conducted on PubMed, Medline, and EMBASE databases using specific Medical Subject Headings terms such as loneliness and genes, neuro- and epigenetics, addiction, affective disorders, alcohol, anti-reward, anxiety, depression, dopamine, cancer, cardiovascular, cognitive, hypodopaminergia, medical, motivation, (neuro)psychopathology, social isolation, and reward deficiency. The narrative literature review yielded recursive collections of scientific and clinical evidence, which were subsequently condensed and summarized in the following key areas: (1) Genetic Antecedents: Exploration of multiple genes mediating reward, stress, immunity and other important vital functions; (2) Genes and Mental Health: Examination of genes linked to personality traits and mental illnesses providing insights into the intricate network of interaction converging on the experience of loneliness; (3) Epigenetic Effects: Inquiry into instances of loneliness and social isolation that are driven by epigenetic methylations associated with negative childhood experiences; and (4) Neural Correlates: Analysis of loneliness-related affective states and cognitions with a focus on hypodopaminergic reward deficiency arising in the context of early life stress, eg, maternal separation, underscoring the importance of parental support early in life. Identification of the individual contributions by various (epi)genetic factors presents opportunities for the creation of innovative preventive, diagnostic, and therapeutic approaches for individuals who cope with persistent feelings of loneliness. The clinical facets and therapeutic prospects associated with the current understanding of loneliness, are discussed emphasizing the relevance of genes and DNA risk polymorphic variants in the context of loneliness-related morbidity.
... P = 0.3218, Figure 1F]. The firing activities of CeA-CRH neurons from CUS-treated BHRs at Days 7 and 14 after the termination of CUS were significantly higher than those in unstressed BHRs [F (5,33) = 4.302, P = 0.004, Figure 1F]. However, in WKY rats, CUS increased the firing activity of CeA-CRH neurons on Day 7, but not Day 14, after CUS termination. ...
... 32 CRH plays an important role in regulating the hormonal, autonomic, and behavioural responses to stress. 33 The CeA is an essential brain region that mediates the stress response. 34 The CeA-CRH neurons project to the locus coeruleus (LC) to modulate the neuronal activity, 35 anxiety-like behaviour, and hippocampus-dependent memory. ...
Aims
Chronic stress is a well-known risk factor for the development of hypertension. However, the underlying mechanisms remain unclear. Corticotropin-releasing hormone (CRH) neurons in the central nucleus of the amygdala (CeA) are involved in the autonomic responses to chronic stress. Here, we determined the role of CeA-CRH neurons in chronic stress-induced hypertension.
Methods and results
Borderline hypertensive rats (BHRs) and Wistar-Kyoto (WKY) rats were subjected to chronic unpredictable stress (CUS). Firing activity and M-currents of CeA-CRH neurons were assessed, and a CRH-Cre-directed chemogenetic approach was used to suppress CeA-CRH neurons. CUS induced a sustained elevation of arterial blood pressure (ABP) and heart rate (HR) in BHRs, while in WKY rats, CUS-induced increases in ABP and HR quickly returned to baseline levels after CUS ended. CeA-CRH neurons displayed significantly higher firing activities in CUS-treated BHRs than unstressed BHRs. Selectively suppressing CeA-CRH neurons by chemogenetic approach attenuated CUS-induced hypertension and decreased elevated sympathetic outflow in CUS-treated BHRs. Also, CUS significantly decreased protein and mRNA levels of Kv7.2 and Kv7.3 channels in the CeA of BHRs. M-currents in CeA-CRH neurons were significantly decreased in CUS-treated BHRs compared with unstressed BHRs. Blocking Kv7 channel with its blocker XE-991 increased the excitability of CeA-CRH neurons in unstressed BHRs but not in CUS-treated BHRs. Microinjection of XE-991 into the CeA increased sympathetic outflow and ABP in unstressed BHRs but not in CUS-treated BHRs.
Conclusions
CeA-CRH neurons are required for chronic stress-induced sustained hypertension. The hyperactivity of CeA-CRH neurons may be due to impaired Kv7 channel activity, which represents a new mechanism involved in chronic stress-induced hypertension.
... The LC-NE is a small pontine nucleus that sends numerous projections throughout the entire central nervous system 16,17 and plays a vital role in the central stress circuitry [18][19][20][21][22] . The LC-NE is ideally suited for upregulating various physiological processes that mobilize energy and promote autonomic adaptation in response to stress [23][24][25][26][27] . Critically, sustained stress responses associated with LC-NE hyper-responsivity have been shown to contribute to chronic anxiety and depression, fear, posttraumatic stress disorder (PTSD), increased risk of hypertension, and cardiovascular disease [28][29][30][31][32][33][34][35] . ...
... Responsivity of LC-NE may thus play a prominent role in determining arousal state and environmental reactivity, making the LC-NE system an ideal neural hub for the facilitation of adaptive behavioral responses to stressors. Dysfunctions or hyperresponsiveness of the LC-NE system have indeed been implicated as a key factor for the development of a variety of pathophysiologic conditions, such as anorexia nervosa, obesity, PTSD, and related affective disorders in humans 25,46 . ...
Individuals may show different responses to stressful events. Here, we investigate the neurobiological basis of stress resilience, by showing that neural responsitivity of the noradrenergic locus coeruleus (LC-NE) and associated pupil responses are related to the subsequent change in measures of anxiety and depression in response to prolonged real-life stress. We acquired fMRI and pupillometry data during an emotional-conflict task in medical residents before they underwent stressful emergency-room internships known to be a risk factor for anxiety and depression. The LC-NE conflict response and its functional coupling with the amygdala was associated with stress-related symptom changes in response to the internship. A similar relationship was found for pupil-dilation, a potential marker of LC-NE firing. Our results provide insights into the noradrenergic basis of conflict generation, adaptation and stress resilience.
... Corticotropin is a 41-mer acid peptide (H-SQEPPISLDLT-FHLLREVLEMTKADQLAQQAHSNRKLLDIA-OH) that plays a role in mediating both endocrine and autonomic responses to stress ( Figure 4) [30,31]. Corticotropin is utilised in the treatment of various specific and inadequately defined steroid-responsive disorders. ...
Peptides continue to gain significant importance in the pharmaceutical arena. Since the unveiling of insulin in 1921, Food and Drug Administration (FDA) has authorised around 100 peptides for various applications. Peptides, although initially derived from endogenous sources, have evolved beyond their natural origins, showcasing favorable therapeutic effectiveness. Medicinal Chemistry has played a pivotal role in synthesising valuable natural peptide analogues, providing synthetic alternatives with therapeutic potential. Furthermore, key chemical modifications have enhanced the stability of peptides and strengthened their interactions with therapeutic targets. For instance, selective modifications have extended the half-life and lessened the frequency of administration while maintaining the desired therapeutic action. In this review, I analyse the FDA approval of natural peptides as well as engineered peptides for diabetes treatment, growth-hormone-releasing hormone (GHRH), cholecystokinin (CCK), adrenocorticotropic hormone (ACTH), and α-melanocyte stimulating hormone (α-MSH) peptide analogues. Attention will be paid towards the structure, mode of action, development journey, FDA authorisation and the adverse effects of these peptides.
... NE is also involved in the capacity to focus attention on relevant inputs. Increased "signal to noise ratio" refers to the fact that when NE is introduced into sensory cortical neurons, the neurons become more responsive to phasic sensory input while their tonic spontaneous discharge patterns remain unaltered or are reduced [10,11]. Over a decade, researchers came to agree that the catecholamine NE played a crucial role in affective disorders like depression because its dysregulation contributed to symptoms like impaired attention, concentration, memory, arousal, and sleep. ...
This study employs Density Functional Theory (DFT) methodology to comprehensively investigate the structural and physicochemical characteristics of epinephrine, a molecule of physiological relevance. By employing DFT approaches, a more precise description of epinephrine's structure and properties is achieved compared to prior studies. A detailed examination of epinephrine's structure and various properties, such as the Highest Occupied Molecular Orbital (HOMO), Lowest Unoccupied Molecular Orbital (LUMO), Band Gap (BG), Density of States (DOS), Fourier-Transform Infrared Spectroscopy (FT-IR), Ultraviolet (UV) absorption, and Natural Bond Orbital (NBO) analysis. Furthermore, we explore non-covalent interactions (NCI) through the examination of Reduced Density Gradient (RDG) and Molecular Electrostatic Potential (MEP) maps. Incorporating FT-IR results, we delve into the vibrational properties of epinephrine, highlighting C-H vibrations at 3700, 3176.20, and 2986.14 cm-1, along with specific vibrational modes of the benzene ring at 1558.43 and 1461.14 cm-1. Additionally, we provide a comprehensive analysis of epinephrine's thermochemical properties at temperatures ranging from 100 to 200 K under constant pressure conditions (1 atm), including optical transitions. This comprehensive investigation enhances our understanding of epinephrine's structure and properties, paving the way for a more profound comprehension of its biological and pharmacological significance.
... To further assess whether Tac2 may act downstream of Brn3b, we performed reverse transcription-quantitative PCR (RT-qPCR) on independent biological samples and confirmed that Brn3b deletion indeed significantly reduces Tac2 expression (approximately 50%, Fig 4C). Two related neuropeptides, tachykinin1 (Tac1) and corticotropin-releasing hormone (Crh), known to mediate effects of stress [35,36], showed no difference between controls and mutants. To determine whether Brn3b+ neurons express Tac2, we performed in situ hybridization with Tac2 probes on brain tissues of the Brn3b GFP/+ mouse (S10 Fig). ...
Defensive responses to visually threatening stimuli represent an essential fear-related survival instinct, widely detected across species. The neural circuitry mediating visually triggered defensive responses has been delineated in the midbrain. However, the molecular mechanisms regulating the development and function of these circuits remain unresolved. Here, we show that midbrain-specific deletion of the transcription factor Brn3b causes a loss of neurons projecting to the lateral posterior nucleus of the thalamus. Brn3b deletion also down-regulates the expression of the neuropeptide tachykinin 2 (Tac2). Furthermore, Brn3b mutant mice display impaired defensive freezing responses to visual threat precipitated by social isolation. This behavioral phenotype could be ameliorated by overexpressing Tac2, suggesting that Tac2 acts downstream of Brn3b in regulating defensive responses to threat. Together, our experiments identify specific genetic components critical for the functional organization of midbrain fear-related visual circuits. Similar mechanisms may contribute to the development and function of additional long-range brain circuits underlying fear-associated behavior.
... NE is also involved in the capacity to focus attention on relevant inputs. Increased "signal to noise ratio" refers to the fact that when NE is introduced into sensory cortical neurons, the neurons become more responsive to phasic sensory input while their tonic spontaneous discharge patterns remain unaltered or are reduced [10,11]. Over a decade, researchers came to agree that the catecholamine NE played a crucial role in affective disorders like depression because its dysregulation contributed to symptoms like impaired attention, concentration, memory, arousal, and sleep. ...
... DL-3,4dihydroxymandelic acid and its derivatives are metabolites of norepinephrine and have antioxidant properties (36). Norepinephrine is an important hormone and neurotransmitter in the human body which is released in higher levels during situations of stress or danger (37). Norepinephrine is also a known neurotransmitter in the Merkel cells located in the skin (38). ...
Detection dogs were trained to detect SARS-CoV-2 infection based on armpit sweat odor. Sweat samples were collected using cotton pads under the armpits of negative and positive human patients, confirmed by qPCR, for periods of 15-30 min. Multiple hospitals and organizations throughout Belgium participated in this study. The sweat samples were stored at −20°C prior to being used for training purposes. Six dogs were trained under controlled atmosphere conditions for 2-3 months. After training, a 7-day validation period was conducted to assess the dogs' performances. The detection dogs exhibited an overall sensitivity of 81%, specificity of 98%, and an accuracy of 95%. After validation, training continued for 3 months, during which the dogs' performances remained the same. Gas chromatography/mass spectrometry (GC/MS) analysis revealed a unique sweat
... Oxytocin, arginine vasopressin, and CRH are the primary hormones regulating human socialisation. While oxytocin typically regulates positive physical contacts and pair-bonding [82], arginine vasopressin and CRH modulate [5] Mood regulation [51] Dopamine [102] Inhibited by light [5] Adrenal norepinephrine [19] Orexin Wakefulness [98] Alertness [73] Melatonin [7] Narcolepsy [75] Attention [91] Dopamine [62] Energy homeostasis [91] M e m o r y [ 91] Serotonin [75] Brain norepinephrine [10] Dopamine Stimulated by light [81] Reward seeking [50] Melatonin [102] Locomotion [59] Motivated behaviour [50] Brain norepinephrine [61] Coordination [59] A p a t h y [ 45] Dysphoria [95] Positive emotions [6] Social play motivation [1] Serotonin Energy balance [41] Controls negative emotions [6] Dopamine [50] Locomotion [41] Depression [60] Brain Fight-flight response [32] Regulation of anger and fear [32] Stress hormones [46] norepinephrine Increase arousal [77] Dopamine and serotonin [61] Social play motivation [1] Oxytocin Prosocial behaviour [82] Calmed mood [12] Stress hormones [43] Positive physical Cooperative behaviour [22] I t s e l f [ 37] contact [37] Reduce stress [36] Pair-bond formation [3] Arginine Aggressive behaviour [9] Controls negative mood disorders Stress hormones [8] vasopressin Circadian rhythms [42] [ 63] ...
Modelling the biology behind animal behaviour has attracted great interest in recent years. Nevertheless, neuroscience and artificial intelligence face the challenge of representing and emulating animal behaviour in robots. Consequently, this paper presents a biologically inspired motivational model to control the biological functions of autonomous robots that interact with and emulate human behaviour. The model is intended to produce fully autonomous, natural, and behaviour that can adapt to both familiar and unexpected situations in human–robot interactions. The primary contribution of this paper is to present novel methods for modelling the robot’s internal state to generate deliberative and reactive behaviour, how it perceives and evaluates the stimuli from the environment, and the role of emotional responses. Our architecture emulates essential animal biological functions such as neuroendocrine responses, circadian and ultradian rhythms, motivation, and affection, to generate biologically inspired behaviour in social robots. Neuroendocrinal substances control biological functions such as sleep, wakefulness, and emotion. Deficits in these processes regulate the robot’s motivational and affective states, significantly influencing the robot’s decision-making and, therefore, its behaviour. We evaluated the model by observing the long-term behaviour of the social robot Mini while interacting with people. The experiment assessed how the robot’s behaviour varied and evolved depending on its internal variables and external situations, adapting to different conditions. The outcomes show that an autonomous robot with appropriate decision-making can cope with its internal deficits and unexpected situations, controlling its sleep–wake cycle, social behaviour, affective states, and stress, when acting in human–robot interactions.
... According to Rehm and Shield, (2019) mental disorders remained among the top ten leading causes of the global burden, with no indication of a global decline since 1990. The anticipated YLLs of mental diseases were extremely low and did not represent the prematurity of persons suffering from mental illnesses (Koob, 1999). In 2016, more than 1 billion people worldwide suffered from mental and addiction diseases. ...
... This and other evidence show that the brain noradrenergic system is the main alarm system that leads to a decrease in autonomic neurovegetatives functions such as food intake and sleep. Much of the evidence available suggests that CRH acts as a neurotransmitter in the LC mediating the noradrenergic activation by various stress conditions (Koob 1999). With respect to Ang II, the presence of AT 2 receptors has been established in LC (Tsutsumi & Saavedra 1991b). ...
En Latinoamérica las regulaciones sobre el uso apropiado de agroquímicos
no son cumplidas estrictamente particularmente en algunos cultivos de
subsistencia familiares como son el de la papa y la cebolla larga, lo cual
genera un riesgo en la aparición de enfermedades asociadas a toxicidad
aguda y crónica. Este estudio tiene como objetivo encontrar la relación
entre la exposición dérmica a pesticidas y la prevalencia de estas
enfermedades. La metodología ha consistido en la determinación de la
cantidad de residuos de pesticidas en la piel basados en datos
experimentales utilizando trazadores inocuos fluorescentes y asociándolo a
las cifras de morbimortalidad de la zona. Se encontró que para algunos
pesticidas como heptacloro E , methiocarb, y mancozeb, entre otros, la
exposición total dérmica (residuos en el traje de protección) es de 140.4,
234 y 304.2 mg respectivamente con una transferencia real, que es la
cantidad residual del pesticida que sobrepasa el traje de protección de
0.8784, 1,464 y 1,9032 mg en su orden, y de que hay un riesgo de que la
exposición a estos pesticidas sea causal, aunque no el único factor, de un
incremento local relativo en la morbimortalidad rural por diabetes mellitus
tipo II, nefropatía crónica no diabética no hipertensiva, síndrome
metabólico y cáncer gástrico. Estos resultados preliminares son útiles para
desarrollar e implementar un programa de buenas prácticas agrícolas con el
fin de reducir dicha exposición en esa comunidad andina, disminuyendo así
el riesgo para la salud de un nivel no medido ni percibido de toxicidad
crónica.
Agradecimientos: Universidad Pedagógica y Tecnológica de Colombia, DIN-
Uptc. Colciencias-Laspau, Universidad Santo Tomás, Tunja. Sociedad de
Farmacología de Chile- Dr. Ramón Sotomayor-Zarate Universidad de Zurich
Universidad de Munich.
Patrocinante: Sotomayor-Zárate, R.
... In the extra-hypothalamic stress system, PTSD is associated with both elevated levels of central norepinephrine (Geracioti et al., 2001;Pan et al., 2018;Southwick et al., 1999) and corticotrophin-releasing factor (CRF) (Baker et al., 1999;Bremner et al., 1997;Sautter et al., 2003), the latter having been suggested to result from diminished feedback inhibition due to hypocortisolemia (see below) (Heim, 2020). In addition to its role in the HPA axis, CRF is a key neuromodulator activating the extra-hypothalamic stress system (Heinrichs and Koob, 2004;Koob, 1999) as is NE (Dunn et al., 2004;Flavin and Winder, 2013), the principal modulator of the acute sympathetic response (Itoi and Sugimoto, 2010;Lambert, 2001;Szabadi, 2008a, 2008b). CRF-ergic activation promotes secretion of NE (Heim and Nemeroff, 2001;Krohg et al., 2008) and, in turn, increased NE can stimulate further CRF release (Dunn et al., 2004;Heim and Nemeroff, 2001). ...
In Posttraumatic Stress Disorder (PTSD), fear and anxiety become dysregulated following psychologically traumatic events. Regulation of fear and anxiety involves both high-level cognitive processes such as cognitive reattribution and low-level, partially automatic memory processes such as fear extinction, safety learning and habituation. These latter processes are believed to be deficient in PTSD. While insomnia and nightmares are characteristic symptoms of existing PTSD, abundant recent evidence suggests that sleep disruption prior to and acute sleep disturbance following traumatic events both can predispose an individual to develop PTSD. Sleep promotes consolidation in multiple memory systems and is believed to also do so for low-level emotion-regulatory memory processes. Consequently sleep disruption may contribute to the etiology of PTSD by interfering with consolidation in low-level emotion-regulatory memory systems. During the first weeks following a traumatic event, when in the course of everyday life resilient individuals begin to acquire and consolidate these low-level emotion-regulatory memories, those who will develop PTSD symptoms may fail to do so. This deficit may, in part, result from alterations of sleep that interfere with their consolidation, such as REM fragmentation, that have also been found to presage later PTSD symptoms. Here, sleep disruption in PTSD as well as fear extinction, safety learning and habituation and their known alterations in PTSD are first briefly reviewed. Then neural processes that occur during the early post-trauma period that might impede low-level emotion regulatory processes through alterations of sleep quality and physiology will be considered. Lastly, recent neuroimaging evidence from a fear conditioning and extinction paradigm in patient groups and their controls will be considered along with one possible neural process that may contribute to a vulnerability to PTSD following trauma.
... In order for LC and PVN neurons to interact reciprocally as part of an excitatory closed loop between the LC and PVN in stressed and prenatally malnourished rats, where tonic neuronal activities in the two nuclei influence each other [52,93,99,100,102,103], in addition to the noradrenergic excitatory connection to the PVN there should be reciprocal excitatory pathways from the PVN to the LC. Available information in this regard indicates that such excitatory connections from the PVN to the LC are primarily provided by CRFergic innervation. ...
A crucial etiological component in fetal programming is early nutrition. Indeed, early undernutrition may cause a chronic increase in blood pressure and cardiovascular diseases, including stroke and heart failure. In this regard, current evidence has sustained several pathological mechanisms involving changes in central and peripheral targets. In the present review, we summarize the neuroendocrine and neuroplastic modifications that underlie maladaptive mechanisms related to chronic hypertension programming after early undernutrition. First, we analyzed the role of glucocorticoids on the mechanism of long-term programming of hypertension. Secondly, we discussed the pathological plastic changes at the paraventricular nucleus of the hypothalamus that contribute to the development of chronic hypertension in animal models of prenatal undernutrition, dissecting the neural network that reciprocally communicates this nucleus with the locus coeruleus. Finally, we propose an integrated and updated view of the main neuroendocrine and central circuital alterations that support the occurrence of chronic increases of blood pressure in prenatally undernourished animals.
... For example, food shortage or antagonistic interactions with conspecifics cause glucocorticoidinduced movement behaviors (reviewed in Goossens et al., 2020), which in turn can have important consequences for individual fitness and gene flow among populations (reviewed in Réale et al., 2007). Across vertebrate taxa, elevations in corticotropin releasing factor (CRF) expression, the tropic hypothalamic hormone of the HPA/I axis, also are associated with anxiety-related behaviors and anorexia through different neural circuits (Crespi and Unkefer, 2014;Koob, 1999). As reviewed in Moyers et al. (2018), circulating levels of glucocorticoids has been both positively and negatively associated with exploratory behaviors across many vertebrate taxa, although the contexts (e.g., resting vs. ACTH-induced HPA/I axis activity) and behavioral assays used across these studies also varies. ...
We assessed the macrogeographic and neuroendocrine correlates of behavioral variation exhibited by juveniles, an important life stage for dispersal, across the expansive range of the wood frog. By rearing animals from eggs in a common garden then using a novel environment test, we uniquely demonstrated differential expression of juvenile behaviors among 16 populations spanning 8° latitude. On the individual level, cluster analysis indicated three major behavior profiles and principal component analysis resolved four unique axes of behavior, including escape, foraging, food intake, feeding efficiency. We found that increased escape behavior was associated with lower adrenocorticotropic hormone (ACTH)-induced circulating corticosterone (CORT) levels, however, foraging and food intake behaviors were not associated with either resting or ACTH-induced CORT. At the population level, the expression of foraging behaviors increased with latitude while food intake behaviors declined with latitude, which raised several hypotheses of eco-evolutionary processes likely driving this variation. Given that these behaviors covary along the same ecological gradient as locally adapted developmental traits, genomic studies in this species could provide deep insights into how HPA/I activity is associated with the eco-evolutionary processes that structure intraspecific variation in morphology and behavior.
... The activity of midbrain DA neurons is known to be involved in spontaneous locomotor activity (Boekhoudt et al., 2016;Koob et al., 1981;Pijnenburg et al., 1975) and reward-related learning behavior (Smith-Roe and Kelley, 2000;Witten et al., 2011). LC NE activity is reported to modulate anxiety-like behavior (Koob, 1999;McCall et al., 2015McCall et al., , 2017. In the present study, the distance traveled in an open field was gradually reduced in TH-Cre KI rats, which was similar to the WT animals, and the distances traveled in the central and peripheral zones were not significantly different between the groups, indicating the normal spontaneous and anxiety-like behaviors in the TH-Cre KI rat strain. ...
Background
Cell groups containing catecholamines provide a useful model to study the molecular and cellular mechanisms underlying the morphogenesis, physiology, and pathology of the central nervous system. For this purpose, it is necessary to establish a system to induce catecholaminergic group-specific expression of Cre recombinase. Recently, we introduced a gene cassette encoding 2 A peptide fused to Cre recombinase into the site between the C-terminus and translational termination codons of the rat tyrosine hydroxylase (TH) open reading frame by the Combi-CRISPR technology, which is a genomic editing method to enable an efficient knock-in (KI) of long DNA sequence into a target site. However, the expression patterns of the transgene and its function as well as the effect of the mutation on the biochemical and behavioral phenotypes in the KI strains have not been characterized yet.
New Method
We aimed to evaluate the usefulness of TH-Cre KI rats as an experimental model for investigating the structure and function of catecholaminergic neurons in the brain.
Results
We detected cell type-specific expression of Cre recombinase and site-specific recombination activity in the representative catecholaminergic groups in the TH-Cre KI rat strains. In addition, we measured TH protein levels and catecholamine accumulation in the brain regions, as well as motor, reward-related, and anxiety-like behaviors, indicating that catecholamine metabolism and general behavior are apparently normal in these KI rats.
Conclusions
TH-Cre KI rat strains produced by the Combi-CRISPR system offer a beneficial model to study the molecular and cellular mechanics for the morphogenesis, physiology, and pathology of catecholamine-containing neurons in the brain.
... Considering these studies, elevated CRH may mediate the effect of stress, including hyperarousal, on increased substance use. As proposed by Koob, elevated CRH levels in the LC increases norepinephrine turnover, including in the amygdala, which subsequently stimulates the release of CRH in a feedforward loop that progressively increases stress response with repeated stressors [42,43]. Multiple types of substances have been shown to activate the HPA axis and catecholaminergic system, including nicotine, cannabis, cocaine, and alcohol [38]. ...
Early childhood maltreatment and other traumatic event experiences (“trauma”) are common among youth, including those with substance use problems including substance use disorders (SUD). Particularly, interpersonal violence is associated with high rates of comorbidity between posttraumatic stress disorder (PTSD) and SUD, and these comorbid disorders exhibit high levels of overlapping symptomatology. Theoretical models proposed to explain the bidirectional relationship between PTSD and SUD include the self-medication hypothesis and susceptibility hypothesis. In this article, we explore neurobiologic changes associated with trauma, PTSD, and SUD that underly dysregulated stress response. Examining lessons learned from recent translational and clinical research, we propose that further elucidating the neurobiologic etiology of comorbid PTSD and SUD will require a collaborative, interdisciplinary approach, including the integration of preclinical and clinical studies, exploration of biologic markers in clinical studies, and accumulation of larger studies and longitudinal studies with the power to study PTSD and SUD. Such research can transform the field and ultimately reduce high rates and costly impairment of co-occurring PTSD and SUD across the lifespan.
... LC NE activity is reported to modulate anxiety-like behavior (Koob, 1999;McCall et al., 2015;McCall et al., 2017). In the present study, the distance travelled in an open field was gradually reduced in TH-Cre KI rats, which was similar to the WT animals, and the distances travelled in the central and peripheral zones were not significantly different between the groups, indicating the normal spontaneous and anxiety-like behaviors in the TH-Cre KI rat strains. ...
Background
Cell groups containing catecholamines provide a useful model to study the molecular and cellular mechanisms underlying the morphogenesis, physiology, and pathology of the central nervous system. For this purpose, it is necessary to establish a system to induce catecholaminergic group-specific expression of Cre recombinase. Recently, we introduced a gene cassette encoding 2A peptide fused to Cre recombinase into the site between the C-terminus and translational termination codons of the rat tyrosine hydroxylase (TH) open reading frame by the Combi -CRISPR technology, which is a genomic editing method to enable an efficient knock-in (KI) of long DNA sequence into a target site. However, the expression patterns of the transgene and its function as well as the effect of the mutation on the biochemical and behavioral phenotypes in the KI strains have not been characterized yet.
New Method
We aimed to evaluate the usefulness of TH-Cre KI rats as an experimental model for investigating the structure and function of catecholaminergic neurons in the brain.
Results
We detected cell type-specific expression of Cre recombinase and site-specific recombination activity in the representative catecholaminergic groups in the TH-Cre KI rat strains. In addition, we measured TH expression level and catecholamine accumulation in the brain regions, and spontaneous locomotion, indicating that catecholamine metabolism and general behavior are apparently normal in these KI rats.
Conclusions
TH-Cre KI rat strains produced by the Combi -CRISPR system offer a beneficial model to study the molecular and cellular mechanics for the morphogenesis, physiology, and pathology of catecholamine-containing neurons in the brain.
... Following HPA axis activation, CRH released by the PVN can activate NE-releasing neurons in the LC. This NE release increases the organism's alertness and induces a rapid behavioural response (Koob, 1999). Chronic stress elicits hyperactivity of LC neurons, which is thought to contribute to stress-related depressive disorders (Seki et al., 2018). ...
Microglia, the resident macrophage cells of the central nervous system (CNS), are involved in a myriad of processes required to maintain CNS homeostasis. These cells are dynamic and can adapt their phenotype and functions to the physiological needs of the organism. Microglia rapidly respond to changes occurring in their microenvironment, such as the ones taking place during stress. While stress can be beneficial for the organism to adapt to a situation, it can become highly detrimental when it turns chronic. Microglial response to prolonged stress may lead to an alteration of their beneficial physiological functions, becoming either maladaptive or pro-inflammatory. In this review, we aim to summarize the effects of chronic stress exerted on microglia through the neuroendocrine system and inflammation at adulthood. We also discuss how these effects of chronic stress could contribute to microglial involvement in neuropsychiatric and sleep disorders, as well as neurodegenerative diseases.
... Although differences in ex vivo and in vivo measurements may occur because of the presence or absence of afferent and efferent connections , these data suggest interactions between the norepinephrine and CRF systems within the CeA. Indeed, it is hypothesised that LC norepinephrine and CeA CRF signals form a 'feed-forward loop' which escalates the brain stress system during alcohol withdrawal (Koob, 1999a). ...
The central nucleus of the amygdala (CeA) is widely implicated as a structure that integrates both appetitive and aversive stimuli. While intrinsic CeA microcircuits primarily consist of GABAergic neurons that regulate amygdala output, a notable feature of the CeA is the heterogeneity of neuropeptides and neuropeptide/neuromodulator receptors that it expresses. There is growing interest in the role of the CeA in mediating psychopathologies, including stress and anxiety states and their interactions with alcohol use disorders. Within the CeA, neuropeptides and neuromodulators often exert pro‐ or anti‐ stress actions, which can influence anxiety and alcohol associated behaviours. In turn, alcohol use can cause adaptions within the CeA, which may render an individual more vulnerable to stress which is a major trigger of relapse to alcohol seeking. This review examines the neurocircuitry, neurochemical phenotypes and how pro‐ and anti‐stress peptide systems act within the CeA to regulate anxiety and alcohol seeking, focusing on preclinical observations from animal models. Furthermore, literature exploring the targeting of genetically defined populations or neuronal ensembles and the role of the CeA in mediating sex differences in stress x alcohol interactions are explored.
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The role of the TAAR1 receptor, one of the trace amine-associated receptors (TAARs) family, in the formation of the behavioral component of the stress response was studied. The behavior of female TAAR1 knockout mice and wild-type (WT) mice was investigated in tests of elevated plus maze and elevated zero maze (EPM and EZM) and forced swimming test (FST) under normal conditions and after uncontrolled restraint stress exposure for 30 min. In the EPM test, the initial level of locomotor and exploratory activity, as well as the anxiety, was identical in both groups of mice. In the EZM test, the initial indicators of anxiety in female TAAR1 KO mice compared to female WT mice were higher, and locomotor activity was lower. When testing mice in the EZM 30 minutes after the end of stress exposure, it was found that the anxiety in female WT mice sharply increased, and the indicators of locomotor activity and exploratory behavior significantly decreased. The behavioral indicators in the EZM test in TAAR1 KO mice before and after stress were identical. A pronounced behavioral component of the stress response was observed in both TAAR1 KO and WT mice during testing in EPM. There were no significant differences between TAAR1 KO and WT mice during testing in EPM four hours after stress exposure. In the FST test the latency to the first immobility was initially longer in TAAR1 KO mice compared to the WT mice, but 24 h after the stress this indicator has significantly decreased. As a result, TAAR1 KO and WT mice no longer differed in all behavioral indicators in the FST. Three weeks after acute restraint stress, both TAAR1 KO and WT groups showed a significant increase in immobility duration and a decrease in latency to the first immobility, however no difference between the both groups of animals were found. Thereby, we found the complete absence of behavioral change immediately after stressor exposure in TAAR1 KO compared to the WT mice.
The role of the TAAR1 receptor, one of the trace amine-associated receptors (TAARs) family, in the formation of the behavioral component of the stress response was studied. The behavior of female TAAR1 knockout (TAAR1 KO) mice and wild-type (WT) mice was investigated in tests of elevated plus maze and elevated zero maze (EPM and EZM) and forced swimming test (FST) under normal conditions and after uncontrolled restraint stress exposure for 30 min. In the EPM test, the initial level of locomotor and exploratory activity, as well as the anxiety, was identical in both groups of mice. In the EZM test, the initial indicators of anxiety in female TAAR1 KO mice compared to female WT mice were higher, and locomotor activity was lower. When testing mice in the EZM 30 minutes after the end of stress exposure, it was found that the anxiety in female WT mice sharply increased, and the indicators of locomotor activity and exploratory behavior significantly decreased. The behavioral indicators in the EZM test in TAAR1 KO mice before and after stress were identical. A pronounced behavioral component of the stress response was observed in both TAAR1 KO and WT mice during testing in EPM. There were no significant differences between TAAR1 KO and WT mice during testing in EPM four hours after stress exposure. In the FST test the latency to the first immobility was initially longer in TAAR1 KO mice compared to the WT mice, but 24 hours after the stress this indicator has significantly decreased. As a result, TAAR1 KO and WT mice no longer differed in all behavioral indicators in the FST. Three weeks after acute restraint stress, both TAAR1 KO and WT groups showed a significant increase in immobility duration and a decrease in latency to the first immobility, however no difference between the both groups of animals were found. Thereby, we found the complete absence of behavioral change immediately after stressor exposure in TAAR1 KO compared to the WT mice.
Locus coeruleus (LC) dysfunction is involved in the pathophysiology of depression; however, the neural circuits and specific molecular mechanisms responsible for this dysfunction remain unclear. Here, it is shown that activation of tyrosine hydroxylase (TH) neurons in the LC alleviates depression‐like behaviors in susceptible mice. The dorsolateral septum (dLS) is the most physiologically relevant output from the LC under stress. Stimulation of the LCTH‐dLSSST innervation with optogenetic and chemogenetic tools bidirectionally can regulate depression‐like behaviors in both male and female mice. Mechanistically, it is found that brain‐derived neurotrophic factor (BDNF), but not norepinephrine, is required for the circuit to produce antidepressant‐like effects. Genetic overexpression of BDNF in the circuit or supplementation with BDNF protein in the dLS is sufficient to produce antidepressant‐like effects. Furthermore, viral knockdown of BDNF in this circuit abolishes the antidepressant‐like effect of ketamine, but not fluoxetine. Collectively, these findings underscore the notable antidepressant‐like role of the LCTH‐dLSSST pathway in depression via BDNF‐TrkB signaling.
Chronic exposure to stress throughout the lifespan has been the focus of many studies on Alzheimer's disease (AD) because of the similarities between the biological mechanisms involved in chronic stress and the pathophysiology of AD. In fact, the earliest abnormality associated with the disease is the presence of phosphorylated tau protein in locus coeruleus neurons, a brain structure highly responsive to stress and perceived threat. Here, we introduce allostatic load as a useful concept for understanding many of the complex, interacting neuropathological changes involved in the AD degenerative process. In response to chronic stress, aberrant tau proteins that begin to accumulate within the locus coeruleus decades prior to symptom onset appear to represent a primary pathological event in the AD cascade, triggering a wide range of interacting brain changes involving neuronal excitotoxicity, endocrine alterations, inflammation, oxidative stress, and amyloid plaque exacerbation. While it is acknowledged that stress will not necessarily be the major precipitating factor in all cases, early tau-induced changes within the locus coeruleus-norepinephrine pathway suggests that a therapeutic window might exist for preventative measures aimed at managing stress and restoring balance within the HPA axis.
Alcohol use disorder (AUD) can be defined by a compulsion to seek and take alcohol, the loss of control in limiting intake, and the emergence of a negative emotional state when access to alcohol is prevented. Alcohol use disorder impacts multiple motivational mechanisms and can be conceptualized as a disorder that includes a progression from impulsivity (positive reinforcement) to compulsivity (negative reinforcement). Compulsive drug seeking that is associated with AUD can be derived from multiple neuroadaptations, but the thesis argued herein is that a key component involves the construct of negative reinforcement. Negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from the dysregulation of specific neurochemical elements that are involved in reward and stress within basal forebrain structures that involve the ventral striatum and extended amygdala, respectively. Specific neurochemical elements in these structures include decreases in reward neurotransmission (e.g., decreases in dopamine and opioid peptide function in the ventral striatum) and the recruitment of brain stress systems (e.g., corticotropin-releasing factor [CRF]) in the extended amygdala, which contributes to hyperkatifeia and greater alcohol intake that is associated with dependence. Glucocorticoids and mineralocorticoids may play a role in sensitizing the extended amygdala CRF system. Other components of brain stress systems in the extended amygdala that may contribute to the negative motivational state of withdrawal include norepinephrine in the bed nucleus of the stria terminalis, dynorphin in the nucleus accumbens, hypocretin and vasopressin in the central nucleus of the amygdala, and neuroimmune modulation. Decreases in the activity of neuropeptide Y, nociception, endocannabinoids, and oxytocin in the extended amygdala may also contribute to hyperkatifeia that is associated with alcohol withdrawal. Such dysregulation of emotional processing may also significantly contribute to pain that is associated with alcohol withdrawal and negative urgency (i.e., impulsivity that is associated with hyperkatifeia during hyperkatifeia). Thus, an overactive brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of AUD. The combination of the loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for a negative emotional state that is responsible for the negative reinforcement that at least partially drives the compulsivity of AUD.KeywordsAlcohol use disorderOpponent processStressExtended amygdalaCorticotropin-releasing factorHypothalamic-pituitary-adrenal axis
Stress is an important risk factor for modern chronic diseases, with distinct influences in males and females. The sex specificity of the mammalian stress response contributes to the sex-dependent development and impacts of coronary artery disease (CAD). Compared to men, women appear to have greater susceptibility to chronic forms of psychosocial stress, extending beyond an increased incidence of mood disorders to include a 2- to 4-fold higher risk of stress-dependent myocardial infarction in women, and up to 10-fold higher risk of Takotsubo syndrome—a stress-dependent coronary-myocardial disorder most prevalent in post-menopausal women. Sex differences arise at all levels of the stress response: from initial perception of stress to behavioural, cognitive, and affective responses and longer-term disease outcomes. These fundamental differences involve interactions between chromosomal and gonadal determinants, (mal)adaptive epigenetic modulation across the lifespan (particularly in early life), and the extrinsic influences of socio-cultural, economic, and environmental factors. Pre-clinical investigations of biological mechanisms support distinct early life programming and a heightened corticolimbic-noradrenaline-neuroinflammatory reactivity in females vs. males, among implicated determinants of the chronic stress response. Unravelling the intrinsic molecular, cellular and systems biological basis of these differences, and their interactions with external lifestyle/socio-cultural determinants, can guide preventative and therapeutic strategies to better target coronary heart disease in a tailored sex-specific manner.
Ecosystems are increasingly involved and influenced by human activities, which are ever-increasing. These activities are mainly due to vehicular, air and sea transportation, thus causing possible repercussions on the fauna that exists there. The aim of this systematic review is to investigate the possible consequences that these activities may have in the field of animal neurobehavior, with special emphasis on the species involved, the most common environment concerned, the noise source and the disturbance that is caused. This research includes articles published in the major databases (PubMed, Cochrane Library, Scopus, Embase, Web of Sciences); the online search yielded 1901 references. After selection, 49 articles (14 reviews and 35 original articles) were finally scrutinized. The main problems that were reported were in relation to movement, reproduction, offspring care and foraging. In live experiments carried out, the repercussions on the marine environment mainly concerned altered swimming, shallower descents, less foraging and an escape reaction for fear of cetaceans and fish. In birds, alterations in foraging, vocalizations and nests were noted; laboratory studies, on the other hand, carried out on small mammals, highlighted spatio-temporal cognitive alterations and memory loss. In conclusion, it appears that greater attention to all ecosystems should be given as soon as possible so as to try to achieve a balance between human activity and the well-being of terrestrial fauna.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
α2a-adrenergic receptor (α2a-AR) agonists are candidate substance use disorder therapeutics due to their ability to recruit noradrenergic autoreceptors to dampen stress system engagement. However, we recently found that postsynaptic α2a-ARs are required for stress-induced reinstatement of cocaine-conditioned behavior. Understanding the ensembles recruited by these postsynaptic receptors (heteroceptors) is necessary to understand noradrenergic circuit control. We utilized a variety of approaches in FosTRAP (Targeted Recombination in Active Populations) mice to define an ensemble of cells activated by the α2a-AR partial agonist guanfacine (“Guansembles”) in the bed nucleus of the stria terminalis (BST/BNST), a region key to stress-induced reinstatement of drug seeking. We define BNST “Guansembles” and show they differ from restraint stress-activated cells. Guanfacine produced inhibition of cAMP-dependent signaling in Guansembles, while chronic restraint stress increased cAMP-dependent signaling. Guanfacine both excited and inhibited aspects of Guansemble neuronal activity. Further, while some stressors produced overall reductions in Guansemble activity, active coping events during restraint stress and exposure to unexpected shocks were both associated with Guansemble recruitment. Using viral tracing, we define a BNST Guansemble afferent network that includes regions involved in the interplay of stress and homeostatic functions. Finally, we show that activation of Guansembles produces alterations in behavior on the elevated plus maze consistent with task-specific anxiety-like behavior. Overall, we define a population of BNST neurons recruited by α2a-AR signaling that opposes the behavioral action of canonical autoreceptor α2a-AR populations and which are differentially recruited by distinct stressors. Moreover, we demonstrate stressor-specific physiological responses in a specific neuronal population.
Disorders in gastrointestinal (GI) motility, visceral hypersensitivity, infection, inflammation, and changes in the gut microbiota are important mechanisms in the pathophysiology of functional gastrointestinal disorders (FGIDs). The concept of the central nervous system (CNS)-GI-gut microbiota axis, by which GI symptoms occur as a result of sensation disorders, includes changes in motility, the combined activation of the autonomic nervous system and CNS, and the effect of gut microbiota. Recently functional magnetic resonance imaging (fMRI) provides the valuable data regarding the mechanisms that controls GI sensation and motility in the CNS. In addition, the areas responsible for emotion or cognition can be visualized by fMRI. In patients with irritable bowel syndrome, GI inflammation caused by the secretion of cytokines with increased intestinal permeability were also found as well as the changes in brain function, and they showed sex/gender differences. One of the reasons why females are more vulnerable to stress responses than males is that females are more sensitive to the locus coeruleus-norepinephrine system, which increases sensitivity to corticotropin-releasing factor (CRF) and stress. When the blood CRF levels increase due to stress, the hypothalamus-pituitary-adrenal (HPA) axis and the norepinephrine arousal system, including adrenocorticotropic hormone (ACTH) and glucocorticoids (e.g., cortisol and corticosterone), are activated, as well as various immune cells such as mast cells. In addition, changes of microbiota and their products were found to be closely related with this gut-brain axis. In this chapter, gut-microbiome-brain axis is briefly reviewed in terms of sex/gender differences.KeywordsGutMicrobiomeBrainAxisSexGender
The aim of the current study was to test the hypothesis that unconditioned and conditioned opioid withdrawal enhance memory consolidation through overlapping neural systems. The reported experiments focussed on noradrenaline (NA) and corticotrophin-releasing factor (CRF) because of the known involvement of these neuromodulators in both opioid withdrawal and memory consolidation. Male Sprague-Dawley rats were implanted with subcutaneous osmotic mini-pumps releasing 3.5 mg/kg/day heroin and received injections of 3 mg/kg naloxone (NLX) to precipitate withdrawal. NLX was preceded by 0.1–0.6 mg/kg lofexidine (LOF) (alpha-2 adrenergic agonist) or 10–20 mg/kg antalarmin (ANT) (CRF1 receptor antagonist), and all injections were administered immediately after (i.e., post-training method) the sample phase of the spontaneous object recognition memory task. The same procedure was repeated 7 days after removal of the mini-pumps. To establish conditioned withdrawal, heroin-exposed rats were confined for 2 h in a context (CS+) following injections of 3 mg/kg NLX and in another context (CS-) following vehicle injections. Seven days after removal mini-pumps, the effects of immediate post-sample exposure to the CS+ (and CS-) preceded by 0.6 mg/kg LOF or 20 mg/kg ANT were assessed. It was found both LOF and ANT blocked the enhancement of object memory by post-sample NLX administration and by exposure to the CS+. These results suggest that pharmacological and psychological withdrawal impact memory storage by activating overlapping NA and CRF systems.
The central noradrenergic system innervates almost all regions of the brain and, as such, is well positioned to modulate many neural circuits implicated in behaviors and physiology underlying substance use disorders. Ample pharmacological evidence demonstrates that α1, α2, and β adrenergic receptors may serve as therapeutic targets to reduce drug –seeking behavior and drug withdrawal symptoms. Further, norepinephrine is a key modulator of the stress response, and stress has been heavily implicated in reinstatement of drug taking. In this review, we discuss recent advances in our understanding of noradrenergic circuitry and noradrenergic receptor signaling in the context of opioid, alcohol, and psychostimulant use disorders.
As an arousal hub region in the brain, the locus coeruleus (LC) has bidirectional connections with the autonomic nervous system. Magnetic resonance imaging (MRI)-based measures of LC structural integrity have been linked to cognition and arousal, but less is known about factors that influence LC structure and function across time. Here, we tested the effects of heart rate variability (HRV) biofeedback, an intervention targeting the autonomic nervous system, on LC MRI contrast and sympathetic activity. Younger and older participants completed daily HRV biofeedback training for five weeks. Those assigned to an experimental condition performed biofeedback involving slow, paced breathing designed to increase heart rate oscillations, whereas those assigned to a control condition performed biofeedback to decrease heart rate oscillations. At the pre- and post-training timepoints, LC contrast was assessed using turbo spin echo MRI scans, and RNA sequencing was used to assess cAMP-responsive element binding protein (CREB)-regulated gene expression in circulating blood cells, an index of sympathetic nervous system signaling. We found that left LC contrast decreased in younger participants in the experimental group, and across younger participants, decreases in left LC contrast were related to the extent to which participants increased their heart rate oscillations during training. Furthermore, decreases in left LC contrast were associated with decreased expression of CREB-associated gene transcripts. On the contrary, there were no effects of biofeedback on LC contrast among older participants in the experimental group. These findings provide novel evidence that in younger adults, HRV biofeedback involving slow, paced breathing can decrease both LC contrast and sympathetic nervous system signaling.
Studies in human subjects have revealed that autonomic responses provide objective and biologically relevant information about cognitive and affective states. Measures of autonomic responses can also be applied to studies of non-human primates, which are neuro-anatomically and physically similar to humans. Facial temperature and pupil size are measured remotely and can be applied to physiological experiments in primates, preferably in a head-fixed condition. However, detailed guidelines for the use of these measures in non-human primates is lacking. Here, we review the neuronal circuits and methodological considerations necessary for measuring and analyzing facial temperature and pupil size in non-human primates. Previous studies have shown that the modulation of these measures primarily reflects sympathetic reactions to cognitive and emotional processes, including alertness, attention, and mental effort, over different time scales. Integrated analyses of autonomic, behavioral, and neurophysiological data in primates are promising methods that reflect multiple dimensions of emotion and could potentially provide tools for understanding the mechanisms underlying neuropsychiatric disorders and vulnerabilities characterized by cognitive and affective disturbances.
Stress system dysfunction is a typical characteristic of acute depression and other mood disorders. The exact pattern of factors predisposing for stress-related mental disorders is yet to be unraveled. However, corticosteroid receptor function plays an important role for appropriate or dysfunctional neuroendocrine responses to stress exposure and hence in resilience or risk for the development and course of both, depression and anxiety disorders. Solid neuroscience data strongly support that both neuropeptides, corticotropin-releasing hormone (CRH) and vasopressin (AVP), are central in coordinating humoral and behavioral adaptation to stress. Other neuropeptides, including oxytocin, neuropeptide S, neuropeptide Y, and orexin, are also considered important contributors.
Attempts to turn neuropeptide biology into treatments for stress-related disorders need to consider that neuropeptide receptors are specific drug targets for certain patient populations rather than universal targets for all patients, like biogenic amine systems. That is why most negative clinical trials testing neuropeptide receptor antagonists have been in fact failed trials by design, because no companion tests were used to identify which patients with depression are most likely to benefit from a specific neuropeptide receptor-targeting drug treatment. Therefore, the most important future research task is discovery and development of appropriate companion tests that will allow the successful transfer of the precious treasure of neuropeptide system-targeting drugs into clinics.
Recently, carbon dots (CDs) have attracted wide attention for their potential use as fluorescence probes in biological and analytical chemistry due to their great stability and high fluorescence quantum yields. In our work, norepinephrine (NE)-derived CDs with green luminescence and an average size of 10 nm were fabricated using a one-step hydrothermal route. As-prepared CDs show a strong emission at a wavelength of 520 nm when excited at 420 nm, and demonstrate pH and concentration dependent fluorescence behaviour. Multiple functional groups on the CDs allow their protonation/deprotonation and thus alter fluorescence intensity and peak position in different pH conditions. Prepared CDs show significant potential to be used as a live-cell imaging agent with long-term photostability. Furthermore, a simple but effective method to determine the concentration of hemoglobin (Hb) in diluted human blood samples was also developed based on the inner filter effect (IFE). The method demonstrates good linearity from 0.01-10 μM, with a limit of determination (LOD) of 52 nM.
Recombinant mouse strain B6.CBA-D13Mit76C (B6-M76C) and B6.CBA-D13Mit76B (B6-M76B), with 5-HT1A receptors with different sensitivities to chronic activation by agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetraline), were created recently. The 5-HT1A receptor is the key regulator in the brain serotonin (5-HT) system and is involved in controlling responses to stress. The studies reported here show that acute emotional stress (restraint for 40 min) increased the expression of the c-fos gene, a marker for stress responses, in the brains of mice of both strains. The stress-induced increase in c-fos expression in the striatum, hypothalamus, and cortex of B6-M76C mice was more marked. Reactions to emotional stress led to increases in the ratio of the serotonin metabolite 5-HIAA (5-hydroxyindoleacetic acid) to 5-HT in the midbrain and hippocampus in both strains. Post-stress increases in the 5-HIAA/5-HT ratio were seen in the hypothalamus of B6-M76C mice and the cortex of B6-M76B mice. The reaction to stress led to decreases in the noradrenaline level in the hippocampus and hypothalamus of B6-M76C mice. The dopamine, noradrenaline, and adrenaline levels and the dopamine/noradrenaline ratio in the adrenals increased in response to stress only in B6-M76C mice. The present study showed that the sympathodrenal system in B6-M76C mice is more sensitive to acute stress. The stress reaction in B6-M76C mice led to increases in noradrenaline and adrenaline contents in adrenal tissue. The increased dopamine/noradrenaline ratio in the adrenals may be evidence of a faster conversion of the intermediate product of catecholamine biosynthesis (dopamine) into noradrenaline and then to adrenaline as a result of acceleration of the biosynthesis process in response to stress in B6-M76C mice. Furthermore, all measures of hypothalamic neuron sensitivity to stress in B6-M76C mice were elevated. Thus, B6-M76C mice are of significant interest for studies of the hypothalamo-hypophyseal-adrenal system with a hyperactive response to stress and may help identify novel biomarkers for stress-related diseases.
This article reviews the antidepressant drugs currently available in Europe and/or the United States from the perspectives of their clinical efficacy, pharmacokinetics, pharmacology, structure–activity relationships, metabolism, and mechanisms of action. The older nonselective monoamine oxidase inhibitors (e.g. phenelzine, tranylcypromine) have largely been replaced by agents that selectively inhibit monoamine oxidase A (e.g. moclobemide) or by inhibitors of serotonin/norepinephrine monoamine transporter reuptake mechanisms. The first generation of such drugs, the tricyclic antidepressants, suffered from a number of dangerous and unpleasant adverse side effects caused by their many other pharmacological actions on the heart and on cholinergic and other monoamine receptors in the brain. Most of the current antidepressants are serotonin‐selective reuptake inhibitors or mixed norepinephrine/serotonin reuptake inhibitors that possess a safer side‐effect profile. These drugs have gained widespread use in the treatment of depression and a number of related psychiatric conditions, including phobias and the treatment of generalized anxiety disorder (GAD). Some agents that act as norepinephrine‐selective reuptake inhibitors (e.g. reboxetine) are also clinically effective and there is considerable overlap between noradrenergic and serotonergic mechanisms in the CNS. Monoamine selectivity can also be altered by the formation of active metabolites in vivo. All approved antidepressants require several weeks of treatment before the maximum clinical benefit is seen. This, although perhaps somewhat agent‐specific, might be attributable to drug‐induced alterations in the expression of receptors in brain and/or alterations in the expression of neurotrophic factors (e.g. brain‐derived neurotrophic factor, vascular endothelial growth factor) associated with changes in neurogenesis in certain brain regions. New approaches to future antidepressant drug discovery include triple reuptake inhibitors, antagonists for glutamate NMDA receptors, corticotrophin‐releasing factor receptors, or agonists/antagonists for galanin receptors. There is particular interest in ketamine analogs and certain other agents (considered as drugs of abuse) because of their rapid and persistent antidepressant effects, especially in treatment‐resistant depression. Agents with mixed mechanisms also are being pursued.
This literature review presents data on the neurobiological basis of posttraumatic disorders, which are an important problem in current psychiatry. Most attention is focused on the evolution of the concepts of combat- related post-traumatic disorders – from psychogenic to biopsychosocial. Data are presented showing that mental pathology provoked by extraordinary stress involves a wide spectrum of biological changes determining the features of the corresponding psychopathological phenomena. Results from neuroimaging, neuroendocrine, biochemical, and immunological studies of post-traumatic stress disorder are discussed. The data presented in this review widen existing concepts of the genesis of post-traumatic stress disorders, which may be relevant for improving approaches to caring for those suffering from severe stress.
Stress-induced activation of locus coeruleus (LC)-norepinephrine (NE) projections to the prefrontal cortex are thought to promote cognitive responses to stressors. LC activation by stressors is modulated by endogenous opioids that restrain LC activation and facilitate a return to baseline activity upon stress termination. Sex differences in this opioid influence could be a basis for sex differences in stress vulnerability. Consistent with this, we recently demonstrated that µ-opioid receptor (MOR) expression is decreased in the female rat LC compared to the male LC, and this was associated with sexually distinct consequences of activating MOR in the LC on cognitive flexibility. Given that the LC-NE system affects cognitive flexibility through its projections to the medial prefrontal cortex (mPFC), the present study quantified and compared the effects of LC-MOR activation on mPFC neural activity in male and female rats. Local field potential (LFPs) were recorded from the mPFC of freely behaving male and female rats before and following local LC microinjection of the MOR agonist, DAMGO, or vehicle. Intra-LC DAMGO altered the LFP power spectrum selectively in male but not female rats, resulting in a time-dependent increase in the power in delta and alpha frequency bands. LC microinfusion of ACSF had no effect on either sex. Together, the results are consistent with previous evidence for decreased MOR function in the female rat LC and demonstrate that this translates to a diminished effect on cortical activity that can account for sex differences in cognitive consequences. Decreased LC-MOR function in females could contribute to greater stress-induced activation of the LC and increased vulnerability of females to hyperarousal symptoms of stress-related neuropsychiatric pathologies.
Corticotropin-releasing factor (CRF) is released in response to various stressors and regulates adrenocorticotropin secretion and glucocorticoid production. In addition to its endocrine functions, CRF acts as a neuromodulator in extra-hypothalamic systems and has been shown to play a role in behavioral responses to stress. CRF overproduction has been implicated in affective disorders such as depression and anorexia nervosa. A transgenic mouse model of CRF overproduction has been developed in order to examine the endocrine and behavioral effects of chronic CRF excess. CRF transgenic animals exhibit endocrine abnormalities involving the hypothalamic-pituitary-adrenal axis such as elevated plasma levels of ACTH and glucocorticoids. The present series of experiments tested the hypothesis that chronic overproduction of CRF throughout the life-span of these animals may lead to an anxiogenic behavioral state. CRF transgenic mice and normal littermate controls were tested by measuring locomotor activity in a novel environment and through the use of an elevated plus-maze as indices of anxiety. CRF transgenic animals exhibited an increase in anxiogenic behavior, an effect known to occur following central administration of CRF in mice and rats. Injection of the CRF antagonist alpha-helical CRF 9-41 into the lateral cerebral ventricles reversed the anxiogenic state observed in the CRF transgenics. This finding supports the possibility that central CRF overproduction may mediate the anxiogenic behavior exhibited in this animal model. Thus, CRF transgenic mice represent a genetic model of CRF overproduction that provides a valuable tool for investigating the long-term effects of CRF excess and dysregulation in the CNS.
Corticotropin-releasing factor (CRF) is the primary factor involved in controlling the release of ACTH from the anterior pituitary and also acts as a neurotransmitter in a variety of brain systems. The actions of CRF are mediated by G-protein coupled membrane bound receptors and a high affinity CRF receptor, CRF1, has been previously cloned and functionally characterized. We have recently isolated a cDNA encoding a second member of the CRF receptor family, designated CRF2, which displays approximately 70% homology at the nucleotide level to the CRF1 receptor and exhibits a distinctive pharmacological profile. The present study utilized in situ hybridization histochemistry to localize the distribution of CRF2 receptor mRNA in rat brain and pituitary gland and compared this with the distribution of CRF1, receptor expression. While CRF1 receptor expression was very high in neocortical, cerebellar, and sensory relay structures, CRF2 receptor expression was generally confined to subcortical structures. The highest levels of CRF2 receptor mRNA in brain were evident within the lateral septal nucleus, the ventromedial hypothalamic nucleus and the choroid plexus. Moderate levels of CRF2 receptor expression were evident in the olfactory bulb, amygdaloid nuclei, the paraventricular and suraoptic nuclei of the hypothalamus, the inferior colliculus and 5-HT-associated raphe nuclei of the midbrain. CRF2-expressing cells were also evident in the bed nucleus of the stria terminalis, the hippocampal formation and anterior and lateral hypothalmic areas. In addition, CRF2 receptor mRNA was also found in cerebral arterioles throughout the brain. Within the pituitary gland, CRF2 receptor mRNA was detectable only at very low levels in scattered cells while CRF1 receptor mRNA was readily detectable in anterior and intermediate lobes. This heterogeneous distribution of CRF1 and CRF2 receptor mRNA suggests distinctive functional roles for each receptor in CRF-related systems. The CRF1 receptor may be regarded as the primary neuroendocrine pituitary CRF receptor and important in cortical, cerebellar and sensory roles of CRF. The anatomical distribution of CRF2 receptor mRNA indicates a role for this novel receptor in hypothalamic neuroendocrine, autonomic and general behavioral actions of central CRF.
Corticotropin releasing factor (CRF) may regulate endocrine, autonomic, and behavioral responses to stress. Evidence indicates that CRF-like immunoreactivity (CRF-LI) is widely distributed throughout the CNS. In this study, the distribution of CRF-LI was determined in 36 rat brain regions by combined radioimmunoassay-micropunch dissection techniques and the effect of stress on CRF-LI was investigated, using a chronic stress model that induces endocrine changes in rats similar to those seen in depressed humans. A control group of rats was handled daily. An acute stress group was subjected to 3 hr of immobilization at 4 degrees C, while a chronic stress group was exposed to unpredictable stressors. Thirty-six brain regions were microdissected by the technique of Palkovits and assayed for CRF-LI, using a specific antiserum to ovine CRF. CRF-LI was detected in most regions. In controls, the highest concentrations were found in the arcuate nucleus/median eminence, the hypothalamic paraventricular (PVN) nucleus, and the periventricular nucleus. The next highest levels were found in the raphe nuclei and dorsal vagal complex. CRF-LI was well represented in the locus coeruleus (LC); in the central, cortical, and medial amygdaloid nuclei; and in the bed nucleus of the stria terminalis. Low concentrations occurred in the hippocampus and cerebrocortical regions. Appreciable concentrations were detected in midbrain and brain stem regions. Acute stress reduced CRF-LI in the arcuate nucleus/median eminence (ME) (by 52%) and in the median preoptic (MPO) nucleus (by 32%) and doubled its concentration in the locus coeruleus.(ABSTRACT TRUNCATED AT 250 WORDS)
CORTICOTROPIN-RELEASING factor (CRF), a peptide first isolated from mammalian brain1, is critical in the regulation of the pituitary–adrenal axis, and in complementary stress-related endocrine, autonomic and behavioural responses2. Fish urotensin I and amphibian sauvagine were considered to be homologues3 of CRF until peptides even more closely related to CRF were identified in these same vertebrate classes4,5. We have characterized another mammalian member of the CRF family and have localized its urotensin-like
immunoreactivity to, and cloned related complementary DNAs from, a discrete rat midbrain region. The deduced protein encodes a peptide that we name urocortin, which is related to urotensin (63% sequence identity) and CRF (45% sequence identity). Synthetic urocortin evokes secretion of adrenocortico-tropic hormone (ACTH) both in vitro and in vivo and binds and activates transfected type-1 CRF receptors6–9, the subtype expressed by pituitary corticotropes. The coincidence of urotensin-like immunoreactivity with type-2 CRF receptors10–13 in
brain, and our observation that urocortin is more potent than CRF at binding and activating type-2 CRF receptors, as well as at inducing c-Fos (an index of cellular activation) in regions enriched in type-2 CRF receptors, indicate that this new peptide could be an endogenous ligand for type-2 CRF receptors.
Intracerebroventricular infusion of corticotropin-releasing factor (CRF) (0.1-1.0 micrograms) produced a pronounced, dose-dependent enhancement of the acoustic startle reflex in rats. This excitatory effect began about 20-30 min after infusion, grew steadily over the 2 hr test period, and lasted at least 6 hr. Higher doses of CRF (10 micrograms) often produced marked facilitation and then inhibition of startle that oscillated repeatedly with a period of 10-20 min. CRF-enhanced startle did not result from an increase in sensitization produced by repetition of the startle stimulus or from a blockade of habituation. Peripheral injections of the autonomic ganglionic blockers hexamethonium (10 mg/kg) or chlorisondamine (3 mg/kg) slightly attenuated the magnitude of CRF-enhanced startle, suggesting a partial role of peripheral sympathetic activation. Intracerebroventricular infusion of the CRF antagonist alpha-helical CRF9-41 (alpha hCRF; 25 or 50 micrograms) blocked CRF-enhanced startle when infused 5 min prior to CRF, indicating a central site of action. CRF-enhanced startle also was reversed when alpha hCRF was given 90 min after infusion of CRF. This suggests that exogenously applied CRF remains in the brain for a very long time after administration or that CRF given exogenously initiates a process that results in a long-lasting activation of endogenous CRF. Because the startle reflex is elevated by both conditioned and unconditioned fear, these data lend further support to the idea that CRF infusion produces a behavioral state that resembles fear or anxiety. Because startle is mediated by a well-defined neural pathway, CRF-enhanced startle may provide a useful behavioral assay to analyze the neural systems upon which exogenous CRF acts to produce its behavioral effects.
Corticotropin-releasing factor (CRF), the recently characterized and synthesized 41-amino acid polypeptide isolated from ovine hypothalami, has been shown to be a potent stimulator of adenohypophyseal beta-endorphin and corticotropin (ACTH) secretion both in vitro and in vivo. In common with other regulatory peptides, CRF has also been demonstrated to possess extra-hypophysiotropic roles. Indeed, intracerebroventricularly (i.c.v.) administered CRF elicits several endocrine and behavioural responses compatible with the concept that this peptide could be a key signal in coordinating the organism's endocrine and behavioural responses to stressful and other adaptive stimuli. We now provide the first evidence for neurally placed CRF in the control of a specific hormone-dependent behavioural response and unequivocally demonstrate an extremely potent suppressive effect of CRF on sexual behaviour in the female rat when microinfused into the arcuate-ventromedial area of the hypothalamus (ARC-VMH) and the mesencephalic central grey (MCG).
The development of our knowledge of the pituitary-adrenal system had its earliest beginnings in the observations of a distinguished London physician, Thomas Addison (1793–1860). In a search for the cause of pernicious anemia, he read a paper to the South London Medical Society entitled “On anemia: disease of the suprarenal capsules.” He described the symptoms of anemia and disease of the suprarenals, which he thought must be related to the anemia, and called the disease “melasma suprarenale.” This initial report was followed some six years later by the publication of Addison’s classic monograph describing disease of the suprarenal capsules. Five of the eleven patients he described had bilateral tuberculosis, others showed evidence of metastatic carcinoma, and one was atrophic with fibrotic changes (Fig. 1). He stated:
THE leading and characteristic features of the morbid state to which I would direct attention are anemia, general languor, debility, remarkable feebleness of the heart’s action, irritability of the stomach, and a peculiar change of colour in the skin occurring in connection with the diseased condition of the suprarenal capsules.
Corticotropin-releasing factor (CRF) is a 41 amino acid peptide with potent activating effects on the pituitary adrenal axis, as shown by its ability to release adrenocorticotropin hormone and β-endorphin from the anterior pituitary (Vale et al. 1981). In accordance with such a role, a large proportion of central nervous system CRF is located within the hypothalamus (Bloom et al. 1982).
The discovery and introduction of valuable new antianxiety agents into clinical psychotherapeutics within the last 20 years was accompanied by a parallel advance in the development of behavioral pharmacology. Behavioral methodology helped to characterize these new agents. At the same time, the interesting and varied properties of these compounds stimulated the development of more comprehensive behavioral techniques so that possible subtle differences among the compounds could be evaluated. In this chapter, we shall review behavioral studies in animals that may shed light upon the therapeutic actions of benzodiazepines and other antianxiety drugs. Although many pharmacologic techniques have been used to study the central nervous system actions of antianxiety agents, e.g., antagonism of pentylene-tetrazol-induced convulsions or footschock-induced fighting, most of the material to be reviewed will involve operant conditioning techniques. The advantages of operant methods, including the use of animals as their own controls because of the availability of stable baselines in trained animals, have been described previously (Cook and Sepinwall, 1975a,b). Some material will be included, however, to indicate the Value of certain nonoperant behavioral procedures for studying anxiolytic compounds.
Corticotropin releasing factor (CRF), a key neuroregulator of the hypothalamic-pituitary-adrenal cortical axis, also displays a broad range of effects on the endocrine, central nervous and immune systems. Having recently characterized the human pituitary CRF receptor by expression cloning of cDNA from a human Cushing's corticotropic adenoma, we report here the structure of the cDNA for a rat brain CRF receptor (rCRF-R) which was cloned by hybridization from a rat brain cDNA library. The sequence of the rCRF-R encodes a 415 amino acid protein comprising seven membrane spanning domains. The rCRF-R is 97% identical at the amino acid level to the human pituitary tumor CRF receptor, differing by only 12 amino acids. When expressed in COSM6 cells, the rCRF-R binds CRF with high affinity (Kd = 1.7 (0.8-3.8)nM). The receptor transduces a CRF stimulated accumulation of intracellular cAMP which is inhibited by the CRF antagonist, alpha helCRF(9-41). These results suggest that the brain expresses a CRF receptor similar to that in the pituitary.
Corticotropin releasing factor (CRF) in the central nervous system appears to have activating properties on behavior and to enhance behavioral responses to stressors. CRF injected into the brain produces increases in arousal as measured by locomotor activation and increased responsiveness to stressful stimuli. These effects of CRF appear to be independent of the pituitary adrenal axis and can be reversed by specific and selective CRF antagonists, α-helical CRF9-41 and D-Phe CRF12-41. Perhaps more importantly, CRF antagonists can reverse behavioral responses to many stressors. These results suggest that endogenous CRF systems in the brain may have a role in mediating behavioral responses to stressors. This system may be particularly important in situations where an organism must mobilize not only the pituitary adrenal system, but also the central nervous system in response to environmental challenge. Clearly, dysfunction in such a fundamental brain-activating system may be the key to a variety of pathophysiological conditions involving abnormal responses to stressors such as anorexia nervosa, anxiety and affective disorders.
Corticotropin-releasing factor injected intracerebroventricularly in a dose of 1 μg produced a prolonged locomotor activation (3 h) in rats previously habituated to the test cage environment. This activation was reversed by α-flupenthixol (intraperitoneally), a dopamine receptor antagonist, only at cataleptic doses and not at all by naloxone (subcutaneously) in doses of 0.02–5.0 mg/kg. The effective dose 50% (ED50) for the α-flupenthixol reversal of locomotor activity induced by corticotropin-releasing factor was 0.13 mg/kg; similar to the 0.14 mg/kg ED50 needed to reverse the locomotor activation produced by caffeine (10 mg/kg s.c). The ED50 necessary to reverse amphetamine (0.75 mg/kg s.c.) locomotion with this drug was 0.07 mg/kg. The results suggest that the corticotropin-releasing factor acts independently of direct activation of the dopamine or opioid peptide systems.
In order to evaluate the action of central nervous system Corticotropin-Releasing Factor (CRF) in the control of feeding behavior the present studies employed a dietary self-selection task sensitive both to overall appetite as well as preferential intake of familiar versus unfamiliar foods. Prior to the diet selection test, one group of nutritionally stressed animals was fed a protein deficient diet in order to increase the preference for unfamiliar foods relative to nutritionally replete subjects. Both CRF (0.05 and 0.5 g ICV) and physical restraint (30 min) attenuated selectively the consumption of a novel food choice by deficient animals without affecting concurrent intake of familiar food. Further, CRF administration did not alter water intake or consumption of either diet by the replete control group suggesting that the peptide produced a stress dependent, enhanced response to novelty without a general effect on appetite. The CRF antagonist,-helical CRF9–41 (1, 5 and 25 g ICV), increased familiar diet consumption in nutritionally deficient subjects without affecting the self-selection pattern or replete controls. Chlordiazepoxide (5 mg/kg) also increased selectively the intake of familiar food suggesting that this action is the anxiolytic complement of the effect of stress in this paradigm. The CRF antagonist (5 and 25 g) reversed the anorexia produced by CRF (0.5 g) as well as that induced by restraint stress. These results favor a direct role for endogenous CRF systems in coordinating the behavioral responses to dietary stress.
The morphological interrelationship between the central serotonergic and hypothalamic corticotropin-releasing factor (CRF) synthesizing systems was studied in the hypothalamic paraventricular nucleus (PVN) of colchicine pretreated male rats. The simultaneous immunocytochemical localization of the transmitter and peptide employed the peroxidase-antiperoxidase complex (PAP) technique using the silver-gold intensified (SGI) and non-intensified forms of the oxidized 3,3′-diaminobenzidine (DAB) chromogen.
The paraventricular nucleus received a moderate serotonergic innervation as compared with other diencephalic structures. The distribution and arborization of serotonergic axons were more prominent in the parvocellular subnuclei than in the magnocellular units of the nucleus. Serotonin containing axons formed terminal bouton and en passant type synapses with dendrites and somata of parvocellular neurons. The immunocytochemical double labelling technique revealed the overlapping of serotonergic axons and CRF-immunoreactive neurons. Vibratome (40 μm) and semithin (1 μm) sections indicated that the interneuronal communication may take place on both dendrites and cell bodies of CRF-immunoreactive neurons. Ultrastructural analysis demonstrated that serotonin-containing terminals formed axo-dendritic and axo-somatic synapses with CRF-immunoreactive neurons. These findings indicate that the central serotonergic neuronal system can influence the function of the pituitary-adrenal endocrine axis via a direct action upon the hypophysiotrophic CRF synthesizing neurons.
The present study determined the behavioural effects of the corticotropin releasing factor (CRF)-related peptides, human/rat
CRF (h/rCRF), ovine CRF (oCRF), sauvagine (SAUV), urotensin I (UT) and the recently discovered neuropeptide, rat urocortin
(rUCN). All of the peptides dose-dependently increased motor activity in a familiar environment and reduced feeding in hungry
rats. There was no apparent relationship between potency/affinity at CRF2 receptors and effects in these two tests. In a comparison of h/rCRF and rUCN upon discrete spontaneous behaviours, both peptides
(3.0 μg ICV) increased activity and grooming, induced a fore-paw tremor and reduced the incidence of motionlessness. However,
h/rCRF reduced motionlessness to a greater extent and was a more potent inducer of defaecation, weight loss, oral movements
and fore-paw tremor than rUCN. In the elevated X maze, both h/rCRF and rUCN (1.0 μg ICV) had anxiogenic-like effects upon
behaviour. In contrast, h/rCRF (1.0 μg ICV), but not rUCN (1.0–10 μg ICV) increased the startle response to an acoustic stimulus.
In summary, all the CRF-related peptides increased motor activity and reduced feeding in rats in a similar manner and both
rUCN and h/rCRF induced anxiogenesis. However, there were some behavioural differences between rUCN and h/rCRF which require
further study. Further pharmacological investigation of the role of CRF receptor subtypes requires the use of subtype selective
antagonists.
The hypothalamic-pituitary-adrenocortical (HPA) axis and the autonomic nervous system are major effector systems that serve to maintain homeostasis during exposure to stressors. In the past decade, interest in neurochemical regulation and in pathways controlling activation of the HPA axis has focused on catecholamines, which are present in high concentrations in specific brain areas—specially in the hypothalamus. The work described in this review has concentrated on the application of in vivo microdialysis in rat brain regions such as the paraventricular nucleus (PVN) of the hypothalamus, the central nucleus of the amygdala (ACE) the bed nucleus of the stria terminalis (BNST), and the posterolateral hypothalamus in order to examine aspects of catecholaminergic function and relationships between altered catecholaminergic function and the HPA axis and sympathoadrenal system activation in stress. Exposure of animals to immobilization (IMMO) markedly and rapidly increases rates of synthesis, release, and metabolism of norepinephrine (NE) in all the brain areas mentioned above and supports previous suggestions that in the PVN NE stimulates release of corticotropin-releasing hormone (CRH). The role of NE in the ACE and the BNST and most other areas possessing noradrenergic innervation remains unclear. Studies involving lower brainstem hemisections show that noradrenergic terminals in the PVN are derived mainly from medullary catecholaminergic groups rather than from the locus ceruleus, which is the main source of NE in the brain. Moreover, the medullary catecholaminergic groups contribute substantially to IMMO-induced noradrenergic activation in the PVN. Data obtained from adrenalectomized rats, with or without glucocorticoid replacement, and from hypercortisolemic rats suggest that glucocorticoids feedback to inhibit CRH release in the PVN, via attenuation of noradrenergic activation. Results from rats exposed to different stressors have indicated substantial differences among stressors in eliciting PVN noradrenergic responses as well as of responses of the HPA, sympathoneural, and adrenomedullary systems. Finally, involvement of other areas that participate in the regulation of the HPA axis such as the ACE, the BNST, and the hippocampus and the importance of stress-induced changes in expression of immediate early genes such as c-fos are discussed.
Previous work has shown that administration of corticotropin-releasing factor (CRF) into the lateral ventricle antagonizes the orexigenic effect of neuropeptide Y (NPY), and central injection of CRF antagonist, α-helical CRF(9–41) enhanced NPY-induced food intake in satiated rats. The aim of the present study was to determine the effects of selective inactivation of hypothalamic CRF neurons on food intake induced by NPY injection and to delinate which hypothalamic nucleus is involved in this NPY/CRF interaction related to the regulation of food intake. Impairment of CRF neuron function by immunotargeting of a ricin A chain toxin with a monoclonal antibody to CRF (CRF-MAb) has been previously reported. Administration of CRF-MAb/toxins into the paraventricular nucleus (PVN) two weeks prior to testing produced markedly enhanced eating induced by injection of NPY into the same nucleus. This effect was accompanied by a 60% decrease in CRF content within the hypothalamus and a 43% decrease of CRF in the median eminence, a site of projection of CRF neurons from the PVN. In contrast, injection of CRF-MAb/toxins into the ventromedial nucleus of the hypothalamus (VMH) did not modify the feeding induced by NPY injection into this hypothalamic area. Systemic pretreatment with the synthetic glucocorticoid dexamethasone at a dose known to downregulate the levels of CRF in the PVN also enhanced the feeding induced by intra-PVN injection of NPY.This suggests that an equilibrium between CRF and NPY neuronal function within the PVN may play an important role in the regulation of food intake. This interactive mechanism may provide some partial explanation of the eating disorders related to stress, in particular anorexia nervosa.
The purpose of this experiment was to investigate whether endogenous corticotropin-releasing factor (CRF) within the paraventricular nucleus of the hypothalamus (PVN) is involved in the alteration of locomotor activity related to a novel, presumably stressful, environment in rats. Impairment of the function of CRF-containing neurons was effected by immunotargeting ricin A chain toxin to these cells with a monoclonal antibody to CRF (CRF-MAb/toxins). CRF-MAb/toxins administered into the PVN 2 weeks prior to testing produced an increase in locomotor activity during exposure to novel environment photocell cages. This behavioral activation was maintained throughout the 120 min experimental session, but was not present when the rats where introduced to the same photocell cages after extensive habituation. These results suggest that the effect induced by CRF-MAb/toxin treatment was related to the exploration of the novel environment, and was not due to a generalized locomotor hyperactivity. This effect was accompanied by a 53% and 61% CRF decrease in the hypothalamus and the median eminence, respectively. Injection of CRF-MAb/toxins into the ventromedial nucleus of the hypothalamus did not modify the locomotor activity in either unfamiliar or familiar conditions. These data suggest that CRF neurons within the PVN may participate not only in the activation of the pituitary adrenal axis associated with stressors but also as physiological mediators of the behavioral responses to stress.
A multicompartment chamber was used to study the investigatory behavior of mice in a novel environment. Restraint stress, subcutaneous morphine (1.75 mg/kg), and ICV corticotropin-releasing factor (CRF; 75 ng) each produced a decreased mean time per contact with novel stimuli. The effect of all three treatments was antagonized by a dose of naloxone that by itself had no significant behavioral effects (0.7–0.75 mg/kg). Naloxone alone at a higher dose (1.25 mg/kg), increased the mean time per contact with the stimuli. These results confirm previous reports of the effects of opiates and stress on this behavior in rats. The similarity of the effects of CRF and stress on the behavioral response to this chamber supports the possibility that CRF may act in the central nervous system to mediate certain behavioral responses in stress.
Release of norepinephrine (NE) and its metabolites in the bed nucleus of the stria terminalis (BNST) was examined using in vivo microdialysis in conscious rats before, during and after 2 h of immobilization. Microdialysate levels of NE and of dihydroxyphenylglycol (DHPG) increased by 170–290% above basal levels during the 1st h of immobilization and decreased gradually thereafter. In contrast, levels of dihydroxyphenylacetic acid (DOPAC) increased gradually over the entire period of immobilization, peaking at 110% above baseline levels. These findings indicate that in rats a single immobilization is attended by increased synthesis, release and reuptake of NE within the BNST. The results are consistent with previous findings relating to stress-induced release of NE in the hypothalamic paraventricular nucleus, central nucleus of the amygdala and cerebral cortex and suggest concurrent noradrenergic activation in several brains centers during acute stress.
Previous work has characterized an anorexic action for endogenous, central nervous system corticotropin-releasing factor (CRF). Central injection of CRF decreases food intake induced pharmacologically by various appetite stimulants and a CRF antagonist attenuates restraint stress anorexia. Also, stressful physiological stimuli that are relevant to ingestive regulation, such as glucoprivation and protein nutrient deficiency activate CRF systems. The present experiments examined the effects of exogenously administered CRF and a CRF antagonist, α-helical CRF(9–41), on spontaneous feeding induced by neuropeptide Y (NPY) and by a tail-pinch stressor. Pretreatment with a low dose of the CRF antagonist (1 μg ICV) enhanced the hyperphagia induced by NPY while reducing the latency to begin feeding and increasing the duration of eating during tail pinch. Higher doses of α-hel CRF (5 and 25 μg ICV) exhibited diminishing or opposite effects. In contract, CRF pretreatment (0.02, 0.1, and 0.5 μg ICV) blocked the acquisition of tail-pinch feeding. Hence, while CRF administration impairs intake in these and other feeding paradigms, α-hel CRF actually facilitated dose dependently the intensity of the feeding response to NPY and tail pinch. These results suggest that endogenous CRF systems may play a role in modulating excessive feeding under conditions of evoked appetite and that brain CRF systems regulate feeding when excessive intake threatens to compromise the performance of other noningestive behaviors.
Introduction of a socially naive male rat into the home territory of a resident counterpart results in agonistic interactions, leading to the rapid social defeat of the intruder. Exposure to the aggressive resident produces a stress-response profile consisting of neuroendocrine activation and coping behaviors such as submission. The present studies examined the dependence of these adaptive responses on endogenous brain Corticotropin-Releasing Factor (CRF), a peptide hormone known to coordinate neuronally mediated- and pituitary-adrenal responses to stress. The elevated Plus-Maze was employed as an animal model of emotionality in which stressors reduce subsequent exploration of open maze arms without walls in favor of enclosed maze arms. A CRF antagonist, a-hel CRF9−41, administered intracerebroventricularly (5 and 25 μg i.c.v.) immediately post-stress and 5 min prior to maze testing reversed the heightened emotionality produced by the resident exposure stressor. This action paralleled that of an anxiolytic dose of the short-acting benzodiazepine, midazolam (1.5 mg/kg i.p.). Intra-amygdaloid administration of lower doses of the CRF antagonist (125, 250 and 500 ng i.c.) also reversed, dose-dependently, the effect of exposure to an aggressive resident without altering the behavior of unstressed control animals. Further, the enhanced release of ACTH and corticosterone following social conflict was not modified over the short term by the intra-amygdaloid dose of CRF antagonist (250 ng i.c.) which was effective in reversing stress-induced hyper-emotionality. These results suggest that limbic system CRF substrates exert an anxiogenic effect on the exploratory behavior of socially defeated rats via a pituitary-adrenal-independent mechanism.
Corticotropin-releasing factor administered intracerebroventricularly produces prolonged elevation of plasma concentrations of epinephrine, norepinephrine and glucose. These hormonal changes are associated with an increase in motor activity and oxygen consumption. No change in body temperature is observed. CRF produces changes in animal physiology that are similar to those observed in response to stress.
These experiments used in vivo microdialysis and high-performance liquid chromatography to examine, in rats, norepinephrine (NE) release in the amygdala induced by footshock and systemic administration of drugs affecting the opioid peptidergic system. A microdialysis probe was inserted into a previously implanted guide cannula aimed at the amygdala and the rat was placed in a box with a stainless-steel grid floor through which a single footshock was delivered. Samples were collected and analyzed at 15-min intervals. Footshock stimulation increased NE levels and the magnitude of the increase varied with footshock intensity. Relative to baseline levels, intensities of 0.3, 0.7 and 1.2 mA (3 s) induced increases of 41, 64 and 97%, respectively. NE levels returned to baseline within 30 min after footshock stimulation. The opioid peptidergic antagonist naloxone (1 mg/kg, i.p.) administered immediately after footshock (0.55 mA for 1 s) potentiated NE release. In contrast, the opioid peptidergic agonist β-endorphin (10 μg/kg, i.p.) administered after the footshock blocked the footshock-induced increase in NE levels. The magnitude of NE release was less when the drugs were administered without prior footshock and when the injections were given 30 min after footshock. The findings are consistent with previous evidence that acute, mildly stressful stimulation induces the release of NE in the amygdala as well as with extensive pharmacological evidence indicating that amygdala NE released by arousing stimulation is involved in regulating memory storage and that the opioid peptidergic system influences memory storage by modulating the release of NE in the amygdala.
Corticotropin-releasing factor (CRF) administered intracerebroventricularly (ICV) to rats and mice has been shown to elicit a variety of behaviors resembling those that occur in stress. In a novel multicompartment chamber, ICV CRF altered the behaviors in a manner closely resembling that observed following a period of restraint. In particular, 75 ng CRF ICV or 30–40 min restraint markedly reduced the time mice spent in contact with novel stimuli. ICV injections of a peptide antagonist of CRF, α-helical CRF9–41, (ahCRF), reversed the effects of restraint on this measure. This effect of ahCRF was dose dependent, with a minimal effective dose of 10 μg. Other behavioral measures appeared normal, and ahCRF did not significantly alter the stimulus-contact time in unrestrained mice. These results provide strong evidence to support the hypothesis that endogenous CRF may be a factor affecting stress-induced changes in exploratory behavior in mice.
Antibodies to synthetic ovine corticotropin releasing factor (CRF) were used to localize nerve fibers and cell bodies in rat brain. Cell bodies, located nera the paraventricular nucleus, send a rich fiber plexus to the median eminence and less dense fiber connections to other hypothalamic and midbrain targets.
Exogenous corticotropin releasing factor (CRF) causes centrally mediated behavioral changes including decreased feeding and increased grooming. These behavioral changes are also seen in response to some stressors. However, the role of endogenous CRF in the behavioral response to stressors has not been investigated fully. We report below our findings on the behavioral effects of alpha-helical CRF (9–41), a recently discovered competitive antagonist of CRF-induced ACTH release. Alpha-helical CRF (9–41) partially reversed the decrement in feeding induced by CRF. Furthermore, the reduction in food intake due to restraint stress was partially reversed by alpha-helical CRF (9–41). These results indicate that changes in endogenous CRF release induced by the restraint Stressor may play a role in stress-induced anorexia.
Evidence supports the idea of two distinct corticotropin-releasing hormone (CRH) systems in the brain: one which is constrained by glucocorticoids and the other which is not. It is this latter system that includes two primary sites (central nucleus of the amygdala and the lateral bed nucleus of the stria terminalis) in which the regulation of CRH gene expression can be disassociated from that of the paraventricular nucleus of the hypothalamus. It is this other system that we think is linked to fear and anxiety and to clinical syndromes (excessively shy fearful children, melancholic depression, post-traumatic stress disorder and self-administration of psychotropic drugs). The excess glucocorticoids and CRH, and the state of anticipatory anxiety, contribute to allostatic load, a new term that refers to the wear and tear on the body and brain arising from attempts to adapt to adversity. © 1998 Published by Elsevier Science Ltd. All rights reserved.
Postprandial administration in the rat of a wide variety of drugs, peptides and toxins suppresses future consumption of a meal of previously unfamiliar but otherwise attractive saccharin-flavored solution. Since the intensity of this conditioned flavor aversion in the rat is sensitive to plasma stress hormone levels, the present study examined the effects on flavor conditioning of corticotropin-releasing factor, a peptide known to be involved in behavioral and hormonal responses to stress. In two-bottle water vs. saccharin choice tests, CRF (0.5 μg ICV) increased significantly the consumption of saccharin solution following a single saccharin/CRF pairing, while a tenfold larger dose of CRF (5 μg ICV) abolished saccharin intake following two saccharin/CRF pairings. Hence, exogenous CRF is capable of inducing both flavor preference and aversion in a dose- and situation-dependent manner. Further, direct neurotropic actions of CRF probably subserve its aversive effect since dexamethasone pretreatment weakened but did not prevent CRF-induced conditioned taste avoidance. These results suggest that at low doses CRF can produce arousal actions that result in taste preference and at higher doses produces aversive effects that are reflected in taste avoidance.
Urocortin was recently cloned from the rat midbrain. Urocortin is a member of the corticotropin releasing factor (CRF) peptide family and shows 45% sequence identity to CRF and 63% sequence identity to urotensin. It binds with a high affinity to CRF1 and CRF2 receptors, resulting in the stimulation of their adenylate cyclase activity. We used a polyclonal antibody against rat urocortin to define the distribution of urocortin-like immunoreactivity in the rat central nervous system. Several immunostained cell bodies were found in the supraoptic, paraventricular, and ventromedial hypothalamic nuclei. A large number of neurons with urocortin-like immunoreactivity were seen in the dorsolateral tegmental nucleus, in the linear and dorsal raphe nuclei, and in the substantia nigra. The most abundant immunoreactive (ir) perikarya were found in the Edinger-Westphal nucleus. Some neurons showed immunoreactivity in the interstitial nucleus of Cajal, the nucleus of Darkeschewitsch, and the periaqueductal gray. A dense immunoreactive fiber network was found in the lateral septal area. Some faintly stained axon terminals were observed among urocortin-ir perikarya in the supraoptic and paraventricular nuclei, in the central and periaqueductal gray, and in the Edinger-Westphal nucleus. No fibers with urocortin-ir were seen in the median eminence or the posterior pituitary. The distribution of urocortin-ir overlapped with the expression of the mRNA for the CRF2 receptor in several brain areas. These data support the hypothesis that this peptide is the endogenous ligand for the CRF2 receptor. Urocortin has been implicated in various endocrine responses, such as blood pressure regulation, as well as in higher cognitive functions.
Corticotropin-releasing factor (CRF) has been shown to have potent central nervous system-activating effects when administered intracerebroventricularly (i.c.v.). In the present experiment, this activating effect was exaggerated by use of a stress-motivated behavioral paradigm. Low doses of CRF (0.01 and 0.1 micrograms/rat) administered i.c.v. facilitated stress-induced fighting. More importantly, alpha-helical CRF-(9-41), a CRF antagonist, blocked stress-induced fighting produced by higher levels of stress. These results suggest that CRF in the central nervous system may have a role in mediating behavioral responses to stress.
The morphological interrelationship between the central serotonergic and hypothalamic corticotropin-releasing factor (CRF) synthesizing systems was studied in the hypothalamic paraventricular nucleus (PVN) of colchicine pretreated male rats. The simultaneous immunocytochemical localization of the transmitter and peptide employed the peroxidase-antiperoxidase complex (PAP) technique using the silver-gold intensified (SGI) and non-intensified forms of the oxidized 3,3'-diaminobenzidine (DAB) chromogen. The paraventricular nucleus received a moderate serotonergic innervation as compared with other diencephalic structures. The distribution and arborization of serotonergic axons were more prominent in the parvocellular subnuclei than in the magnocellular units of the nucleus. Serotonin containing axons formed terminal bouton and en passant type synapses with dendrites and somata of parvocellular neurons. The immunocytochemical double labelling technique revealed the overlapping of serotonergic axons and CRF-immunoreactive neurons. Vibratome (40 micron) and semithin (1 micron) sections indicated that the interneuronal communication may take place on both dendrites and cell bodies of CRF-immunoreactive neurons. Ultrastructural analysis demonstrated that serotonin-containing terminals formed axo-dendritic and axo-somatic synapses with CRF-immunoreactive neurons. These findings indicate that the central serotonergic neuronal system can influence the function of the pituitary-adrenal endocrine axis via a direct action upon the hypophysiotrophic CRF synthesizing neurons.
To assess whether centrally administered corticotropin-releasing hormone (CRH) modulates behavioral and antinociceptive effects of exposure to a novel environment, vehicle or 0.03, 0.3, or 3.0 micrograms of CRH was administered intracerebroventricularly (ICV) to rats, which were then tested under novel or familiar conditions. Novelty decreased sleeping and grooming and increased rearing, walking, and latency to respond on the hot-plate test of analgesia. CRH increased grooming and walking, decreased rearing and sleeping, and had no effect in the hot-plate test. The lowest dose was without effect on any measure; otherwise, CRH effects generally were dose-dependent. There was no evidence that CRH selectively enhanced or interfered with novelty-induced behavioral changes; it influenced behavior to the same degree in both test conditions. However, test condition selectively modulated the degree of peptide-induced self-gnawing and burrowing.
The behavioral and EEG effects of rat and ovine corticotropin releasing factor (r- and o-CRF) were compared. Both peptides were injected intracerebroventricularly into rats through chronically implanted cannulae. At the doses of 0.1 and 1 microgram both peptides activated the EEG and stimulated motor activity. At the dose of 10 micrograms they produced spiking activity. However, while o-CRF-induced spiking activity was present both in the hippocampus and in the cortical leads and was associated with generalized myoclonic movements, that induced by r-CRF was confined in the hippocampus and was not accompanied by myoclonic movements. Spiking activity induced by r-CRF was suppressed by verapamil, but was not influenced by naloxone.
Corticotropin-releasing factor (CRF) has potent behavioral effects when administered intracerebroventricularly to rats. CRF and its receptors are found in an uneven distribution in the brain. In an effort to localize the site of the anorectic effect of CRF, exogenous CRF or saline was injected into cannulas directed toward the paraventricular hypothalamic nucleus (PVN), lateral hypothalamus, ventromedial hypothalamus, globus pallidus, or striatum of rats. CRF decreased food intake only when injected into the PVN. In subsequent experiments PVN injections of CRF were shown to (1) increase grooming and movement; (2) not induce a conditioned taste aversion to saccharin in a single bottle test; and (3) inhibit the increase in feeding induced by injections of norepinephrine into the PVN. These results suggest that CRF induces not only anorexia, but also increased movement and grooming by action in the PVN. Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/27370/1/0000396.pdf
A theory of the response to chronic intermittent stress, intergating many diverse studies, is presented. Chronic intermittent stress is presumed to be the type of stress most frequently encountered and most likely to cause physiological changes which predispose an organism to tissue damage. The theory states that all organisms are genetically predisposed to adapt to stress and that the physiological pattern of adaptation is similar across species. This pattern consists of a conditioned endocrine response before the stressor is presented accompanied by a decrease in arousal during the stress. These changes occur because the organism is predisposed to learn cues predictive of stress and to assess the threat potential of the stressor. This pattern is adaptive because it conserves resources and promotes homeostasis. Maladaptation is discussed in terms of failure to learn situational expectancies and appropriate responses. Implications of this theoretical perspective are examined.
Intracerebroventricularly administered alpha-helical CRF9-41, a corticotropin-releasing factor (CRF) receptor antagonist, is known to reduce a variety of stress-induced behavioral responses. This study examined in rats whether antagonism of CRF receptors in the region of locus coeruleus (LC) plays a role in reducing freezing induced by electric foot shock. Freezing is a well-characterized defensive response to stress and has been demonstrated to index an animal's degree of fear. A CRF-receptor antagonist, alpha-helical CRF9-41, bilaterally infused into the LC significantly reduced the duration of freezing at a dose as low as 0.20 micrograms. Additional experiments confirmed that 0.20 micrograms of alpha-helical CRF9-41 significantly reduced the duration of freezing only when cannulae were within the LC or in regions bordering the nucleus. Antagonist-treated rats with cannulae that did not impinge on the LC exhibited freezing at levels not different from vehicle-treated animals. These results strongly implicate CRF receptors located in the LC region in influencing the display of stress-induced behavior.